Статті в журналах: "LIM Protein"

1

Matthews, Jacqueline M., Mugdha Bhati, Vanessa J. Craig, Janet E. Deane, Cy Jeffries, Christopher Lee, Amy L. Nancarrow, Daniel P. Ryan, and Margaret Sunde. "Competition between LIM-binding domains." Biochemical Society Transactions 36, no. 6 (November 19, 2008): 1393–97. http://dx.doi.org/10.1042/bst0361393.

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LMO (LIM-only) and LIM-HD (LIM-homeodomain) proteins form a family of proteins that is required for myriad developmental processes and which can contribute to diseases such as T-cell leukaemia and breast cancer. The four LMO and 12 LIM-HD proteins in mammals are expressed in a combinatorial manner in many cell types, forming a transcriptional ‘LIM code’. The proteins all contain a pair of closely spaced LIM domains near their N-termini that mediate protein–protein interactions, including binding to the ∼30-residue LID (LIM interaction domain) of the essential co-factor protein Ldb1 (LIM domain-binding protein 1). In an attempt to understand the molecular mechanisms behind the LIM code, we have determined the molecular basis of binding of LMO and LIM-HD proteins for Ldb1LID through a series of structural, mutagenic and biophysical studies. These studies provide an explanation for why Ldb1 binds the LIM domains of the LMO/LIM-HD family, but not LIM domains from other proteins. The LMO/LIM-HD family exhibit a range of affinities for Ldb1, which influences the formation of specific functional complexes within cells. We have also identified an additional LIM interaction domain in one of the LIM-HD proteins, Isl1. Despite low sequence similarity to Ldb1LID, this domain binds another LIM-HD protein, Lhx3, in an identical manner to Ldb1LID. Through our and other studies, it is emerging that the multiple layers of competitive binding involving LMO and LIM-HD proteins and their partner proteins contribute significantly to cell fate specification and development.

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2

El Omari, Kamel, Sarah J. Hoosdally, Kapil Tuladhar, Dimple Karia, Paresh Vyas, Roger Patient, Catherine Porcher, and Erika J. Mancini. "Structure of the leukemia oncogene LMO2: implications for the assembly of a hematopoietic transcription factor complex." Blood 117, no. 7 (February 17, 2011): 2146–56. http://dx.doi.org/10.1182/blood-2010-07-293357.

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Abstract The LIM only protein 2 (LMO2) is a key regulator of hematopoietic stem cell development whose ectopic expression in T cells leads to the onset of acute lymphoblastic leukemia. Through its LIM domains, LMO2 is thought to function as the scaffold for a DNA-binding transcription regulator complex, including the basic helix-loop-helix proteins SCL/TAL1 and E47, the zinc finger protein GATA-1, and LIM-domain interacting protein LDB1. To understand the role of LMO2 in the formation of this complex and ultimately to dissect its function in normal and aberrant hematopoiesis, we solved the crystal structure of LMO2 in complex with the LID domain of LDB1 at 2.4 Å resolution. We observe a largely unstructured LMO2 kept in register by the LID binding both LIM domains. Comparison of independently determined crystal structures of LMO2 reveals large movements around a conserved hinge between the LIM domains. We demonstrate that such conformational flexibility is necessary for binding of LMO2 to its partner protein SCL/TAL1 in vitro and for the function of this complex in vivo. These results, together with molecular docking and analysis of evolutionarily conserved residues, yield the first structural model of the DNA-binding complex containing LMO2, LDB1, SCL/TAL1, and GATA-1.

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3

Robertson, Neil O., Ngaio C. Smith, Athina Manakas, Mahiar Mahjoub, Gordon McDonald, Ann H. Kwan, and Jacqueline M. Matthews. "Disparate binding kinetics by an intrinsically disordered domain enables temporal regulation of transcriptional complex formation." Proceedings of the National Academy of Sciences 115, no. 18 (April 16, 2018): 4643–48. http://dx.doi.org/10.1073/pnas.1714646115.

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Intrinsically disordered regions are highly represented among mammalian transcription factors, where they often contribute to the formation of multiprotein complexes that regulate gene expression. An example of this occurs with LIM-homeodomain (LIM-HD) proteins in the developing spinal cord. The LIM-HD protein LHX3 and the LIM-HD cofactor LDB1 form a binary complex that gives rise to interneurons, whereas in adjacent cell populations, LHX3 and LDB1 form a rearranged ternary complex with the LIM-HD protein ISL1, resulting in motor neurons. The protein–protein interactions within these complexes are mediated by ordered LIM domains in the LIM-HD proteins and intrinsically disordered LIM interaction domains (LIDs) in LDB1 and ISL1; however, little is known about how the strength or rates of binding contribute to complex assemblies. We have measured the interactions of LIM:LID complexes using FRET-based protein–protein interaction studies and EMSAs and used these data to model population distributions of complexes. The protein–protein interactions within the ternary complexes are much weaker than those in the binary complex, yet surprisingly slow LDB1:ISL1 dissociation kinetics and a substantial increase in DNA binding affinity promote formation of the ternary complex over the binary complex in motor neurons. We have used mutational and protein engineering approaches to show that allostery and modular binding by tandem LIM domains contribute to the LDB1LID binding kinetics. The data indicate that a single intrinsically disordered region can achieve highly disparate binding kinetics, which may provide a mechanism to regulate the timing of transcriptional complex assembly.

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4

Cai, Ying, Zhixiong Xu, Lalitha Nagarajan, and Stephen J. Brandt. "Single-Stranded DNA-Binding Proteins (SSBPs) Regulate the Abundance of the LIM-Homeodomain Protein LHX2 and Augment Its Transcriptional Activity." Blood 110, no. 11 (November 16, 2007): 1239. http://dx.doi.org/10.1182/blood.v110.11.1239.1239.

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Abstract A small family of proteins with putative single-stranded DNA-binding activity has been shown to augment the biological actions of LIM-homeodomain (LIM-HD) transcription factors through the mediation of the LIM domain-binding protein LDB1. We recently established that two of these SSBPs, Ssbp2 and Ssbp3, were components of an E-box-GATA DNA-binding complex in murine erythroid progenitors containing transcription factors Tal1, E2A, and Gata-1 and LIM-only protein Lmo2 and showed that Ssbp2 stimulated E box-GATA DNA-binding activity by inhibiting Ldb1 ubiquitination and Ldb1 and Lmo2 turnover (Genes & Dev.21:942–955, 2007). Since LIM-HD proteins are substrates of different E3 ubiquitin ligases than LIM-only proteins and have the additional property of binding DNA, we sought to determine the effect of SSBPs on LIM-HD expression and function. Using the prototype LIM-HD protein Lhx2 and one of its best-characterized target genes, Cga, for analysis, we found that an Ssbp3-, Ldb1-, and Lhx2-containing complex associated with an Lhx2 binding element in the Cga promoter in vitro and in mouse pituitary cells (alphaT3-1 cell line) in vivo. We then showed that enforced expression of Ssbp2 and Ssbp3 in alphaT3-1 cells increased Lhx2 and Ldb1 protein abundance, Lhx2 DNA-binding activity, and Cga expression and augmented Lhx2 transcriptional activity in an Ldb1-dependent fashion. While Lhx2-Ldb1-Ssbp3 DNA-binding activity increased in Ssbp3- relative to vector-transfected cells, the affinity of this complex for DNA was unaltered. Similar to the effect of Ssbp2 on Lmo2 in murine erythroleukemia (MEL) cells, overexpressed Ssbp3 reduced Lhx2 protein turnover in cycloheximide-treated alphaT3-1 cells without affecting Lhx2 RNA levels. In contrast, knockdown of endogenous Ssbp3, but not Ssbp2 which is expressed at much lower levels in these cells, reduced Lhx2 and Ldb1 abundance, Lhx2 DNA-binding activity, Lhx2, Ldb1, and Ssbp3 loading onto the Cga promoter, Cga promoter activity, and endogenous Cga gene expression. Significantly, neither overexpression nor knockdown of Ssbp2 in MEL cells, which express both the LIM-only protein Lmo2 and LIM-HD protein Lhx2, affected Lhx2 protein abundance, and Lhx2 DNA-binding activity was undetectable in nuclear extracts from these cells despite the presence of immunoreactive Lhx2. These studies indicate that SSBP augmentation of LIM-HD function results from Ldb1-mediated inhibition of LIM-HD protein turnover and increased assembly of a LIM-HD/LDB1/SSBP DNA-binding complex. The much greater affinity for LDB1 of LIM-only compared to LIM-HD proteins is likely a major determinant of the SSBP effect on LIM-HD protein abundance. Finally, these findings are consistent with cell type-specific contributions of different SSBPs, even for similar LDB1-dependent actions.

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5

Jurata, L. W., and G. N. Gill. "Functional analysis of the nuclear LIM domain interactor NLI." Molecular and Cellular Biology 17, no. 10 (October 1997): 5688–98. http://dx.doi.org/10.1128/mcb.17.10.5688.

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LIM homeodomain and LIM-only (LMO) transcription factors contain two tandemly arranged Zn2+-binding LIM domains capable of mediating protein-protein interactions. These factors have restricted patterns of expression, are found in invertebrates as well as vertebrates, and are required for cell type specification in a variety of developing tissues. A recently identified, widely expressed protein, NLI, binds with high affinity to the LIM domains of LIM homeodomain and LMO proteins in vitro and in vivo. In this study, a 38-amino-acid fragment of NLI was found to be sufficient for the association of NLI with nuclear LIM domains. In addition, NLI was shown to form high affinity homodimers through the amino-terminal 200 amino acids, but dimerization of NLI was not required for association with the LIM homeodomain protein Lmxl. Chemical cross-linking analysis revealed higher-order complexes containing multiple NLI molecules bound to Lmx1, indicating that dimerization of NLI does not interfere with LIM domain interactions. Additionally, NLI formed complexes with Lmx1 on the rat insulin I promoter and inhibited the LIM domain-dependent synergistic transcriptional activation by Lmx1 and the basic helix-loop-helix protein E47 from the rat insulin I minienhancer. These studies indicate that NLI contains at least two functionally independent domains and may serve as a negative regulator of synergistic transcriptional responses which require direct interaction via LIM domains. Thus, NLI may regulate the transcriptional activity of LIM homeodomain proteins by determining specific partner interactions.

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6

Goyal, Rakesh K., Phoebe Lin, Josna Kanungo, Aimee S. Payne, Anthony J. Muslin, and Gregory D. Longmore. "Ajuba, a Novel LIM Protein, Interacts with Grb2, Augments Mitogen-Activated Protein Kinase Activity in Fibroblasts, and Promotes Meiotic Maturation of Xenopus Oocytes in a Grb2- and Ras-Dependent Manner." Molecular and Cellular Biology 19, no. 6 (June 1, 1999): 4379–89. http://dx.doi.org/10.1128/mcb.19.6.4379.

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ABSTRACT LIM domain-containing proteins contribute to cell fate determination, the regulation of cell proliferation and differentiation, and remodeling of the cell cytoskeleton. These proteins can be found in the cell nucleus, cytoplasm, or both. Whether and how cytoplasmic LIM proteins contribute to the cellular response to extracellular stimuli is an area of active investigation. We have identified and characterized a new LIM protein, Ajuba. Although predominantly a cytosolic protein, in contrast to other like proteins, it did not localize to sites of cellular adhesion to extracellular matrix or interact with the actin cytoskeleton. Removal of the pre-LIM domain of Ajuba, including a putative nuclear export signal, led to an accumulation of the LIM domains in the cell nucleus. The pre-LIM domain contains two putative proline-rich SH3 recognition motifs. Ajuba specifically associated with Grb2 in vitro and in vivo. The interaction between these proteins was mediated by either SH3 domain of Grb2 and the N-terminal proline-rich pre-LIM domain of Ajuba. In fibroblasts expressing Ajuba mitogen-activated protein kinase activity persisted despite serum starvation and upon serum stimulation generated levels fivefold higher than that seen in control cells. Finally, when Ajuba was expressed in fully developed Xenopus oocytes, it promoted meiotic maturation in a Grb2- and Ras-dependent manner.

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7

Guy, Pamela M., Daryn A. Kenny та Gordon N. Gill. "The PDZ Domain of the LIM Protein Enigma Binds to β-Tropomyosin". Molecular Biology of the Cell 10, № 6 (червень 1999): 1973–84. http://dx.doi.org/10.1091/mbc.10.6.1973.

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PDZ and LIM domains are modular protein interaction motifs present in proteins with diverse functions. Enigma is representative of a family of proteins composed of a series of conserved PDZ and LIM domains. The LIM domains of Enigma and its most related family member, Enigma homology protein, bind to protein kinases, whereas the PDZ domains of Enigma and family member actin-associated LIM protein bind to actin filaments. Enigma localizes to actin filaments in fibroblasts via its PDZ domain, and actin-associated LIM protein binds to and colocalizes with the actin-binding protein α-actinin-2 at Z lines in skeletal muscle. We show that Enigma is present at the Z line in skeletal muscle and that the PDZ domain of Enigma binds to a skeletal muscle target, the actin-binding protein tropomyosin (skeletal β-TM). The interaction between Enigma and skeletal β-TM was specific for the PDZ domain of Enigma, was abolished by mutations in the PDZ domain, and required the PDZ-binding consensus sequence (Thr-Ser-Leu) at the extreme carboxyl terminus of skeletal β-TM. Enigma interacted with isoforms of tropomyosin expressed in C2C12 myotubes and formed an immunoprecipitable complex with skeletal β-TM in transfected cells. The association of Enigma with skeletal β-TM suggests a role for Enigma as an adapter protein that directs LIM-binding proteins to actin filaments of muscle cells.

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8

Johnson, J. D., W. Zhang, A. Rudnick, W. J. Rutter, and M. S. German. "Transcriptional synergy between LIM-homeodomain proteins and basic helix-loop-helix proteins: the LIM2 domain determines specificity." Molecular and Cellular Biology 17, no. 7 (July 1997): 3488–96. http://dx.doi.org/10.1128/mcb.17.7.3488.

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LIM-homeodomain proteins direct cellular differentiation by activating transcription of cell-type-specific genes, but this activation requires cooperation with other nuclear factors. The LIM-homeodomain protein Lmx1 cooperates with the basic helix-loop-helix (bHLH) protein E47/Pan-1 to activate the insulin promoter in transfected fibroblasts. In this study, we show that two proteins originally called Lmx1 are the closely related products of two distinct vertebrate genes, Lmx1.1 and Lmx1.2. We have used yeast genetic systems to delineate the functional domains of the Lmx1 proteins and to characterize the physical interactions between Lmx1 proteins and E47/Pan-1 that produce synergistic transcriptional activation. The LIM domains of the Lmx1 proteins, and particularly the second LIM domain, mediate both specific physical interactions and transcriptional synergy with E47/Pan-1. The LIM domains of the LIM-homeodomain protein Isl-1, which cannot mediate transcriptional synergy with E47/Pan-1, do not interact with E47/Pan-1. In vitro studies demonstrate that the Lmx1.1 LIM2 domain interacts specifically with the bHLH domain of E47/Pan-1. These studies provide the basis for a model of the assembly of LIM-homeodomain-containing complexes on DNA elements that direct cell-type-restricted transcription in differentiated tissues.

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9

Jo, Kiwon, Bart Rutten, Robert C. Bunn, and David S. Bredt. "Actinin-Associated LIM Protein-Deficient Mice Maintain Normal Development and Structure of Skeletal Muscle." Molecular and Cellular Biology 21, no. 5 (March 1, 2001): 1682–87. http://dx.doi.org/10.1128/mcb.21.5.1682-1687.2001.

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ABSTRACT The actinin-associated LIM protein, ALP, is the prototype of a large family of proteins containing an N-terminal PDZ domain and a C-terminal LIM domain. These PDZ-LIM proteins are components of the muscle cytoskeleton and occur along the Z lines owing to interaction of the PDZ domain with the spectrin-like repeats of α-actinin. Because PDZ and LIM domains are typically found in proteins that mediate cellular signaling, PDZ-LIM proteins are suspected to participate in muscle development. Interestingly the ALP gene occurs at 4q35 near the heterochromatic region mutated in facioscapulohumeral muscular dystrophy, indicating a possible role for ALP in this disease. Here, we describe the generation and analysis of mice lacking the ALP gene. Surprisingly, the ALP knockout mice show no gross histological abnormalities and maintain sarcolemmal integrity as determined by serum pyruvate kinase assays. The absence of a dystrophic phenotype in these mice suggests that down-regulation of ALP does not participate in facioscapulohumeral muscular dystrophy. These data suggest that ALP does not participate in muscle development or that an alternative PDZ-LIM protein can compensate for the lack of ALP.

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10

Rath, Nibedita, Zhishan Wang, Min Min Lu, and Edward E. Morrisey. "LMCD1/Dyxin Is a Novel Transcriptional Cofactor That Restricts GATA6 Function by Inhibiting DNA Binding." Molecular and Cellular Biology 25, no. 20 (October 15, 2005): 8864–73. http://dx.doi.org/10.1128/mcb.25.20.8864-8873.2005.

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ABSTRACT The activity of GATA factors is regulated, in part, at the level of protein-protein interactions. LIM domain proteins, first defined by the zinc finger motifs found in the Lin11, Isl-1, and Mec-3 proteins, act as coactivators of GATA function in both hematopoietic and cardiovascular tissues. We have identified a novel GATA-LIM interaction between GATA6 and LMCD1/dyxin. The LIM domains and cysteine-rich domains in LMCD1/dyxin and the carboxy-terminal zinc finger of GATA6 mediate this interaction. Expression of LMCD1/dyxin is remarkably similar to that of GATA6, with high-level expression observed in distal airway epithelium of the lung, vascular smooth muscle, and myocardium. In contrast to other GATA-LIM protein interactions, LMCD1/dyxin represses GATA6 activation of both lung and cardiac tissue-specific promoters. Electrophoretic mobility shift and chromatin immunoprecipitation assays show that LMCD1/dyxin represses GATA6 function by inhibiting GATA6 DNA binding. These data reveal an interaction between GATA6 and LMCD1/dyxin and demonstrate a novel mechanism through which LIM proteins can assert their role as transcriptional cofactors of GATA proteins.

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11

O'Keefe, D. D., S. Thor, and J. B. Thomas. "Function and specificity of LIM domains in Drosophila nervous system and wing development." Development 125, no. 19 (October 1, 1998): 3915–23. http://dx.doi.org/10.1242/dev.125.19.3915.

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LIM domains are found in a variety of proteins, including cytoplasmic and nuclear LIM-only proteins, LIM-homeodomain (LIM-HD) transcription factors and LIM-kinases. Although the ability of LIM domains to interact with other proteins has been clearly established in vitro and in cultured cells, their in vivo function is unknown. Here we use Drosophila to test the roles of the LIM domains of the LIM-HD family member Apterous (Ap) in wing and nervous system development. Using a rescuing assay of the ap mutant phenotype, we have found that the LIM domains are essential for Ap function. Furthermore, expression of LIM domains alone can act in a dominant-negative fashion to disrupt Ap function. The Ap LIM domains can be replaced by those of another family member to generate normal wing structure, but LIM domains are not interchangeable during axon pathfinding of the Ap neurons. This suggests that the Ap LIM domains mediate different protein interactions in different developmental processes, and that LIM domains can participate in conferring specificity of target gene selection.

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12

Cuppen, Edwin, Herlinde Gerrits, Barry Pepers, Bé Wieringa, and Wiljan Hendriks. "PDZ Motifs in PTP-BL and RIL Bind to Internal Protein Segments in the LIM Domain Protein RIL." Molecular Biology of the Cell 9, no. 3 (March 1998): 671–83. http://dx.doi.org/10.1091/mbc.9.3.671.

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The specificity of protein–protein interactions in cellular signaling cascades is dependent on the sequence and intramolecular location of distinct amino acid motifs. We used the two-hybrid interaction trap to identify proteins that can associate with the PDZ motif-rich segment in the protein tyrosine phosphatase PTP-BL. A specific interaction was found with the Lin-11, Isl-1, Mec-3 (LIM) domain containing protein RIL. More detailed analysis demonstrated that the binding specificity resides in the second and fourth PDZ motif of PTP-BL and the LIM domain in RIL. Immunohistochemistry on various mouse tissues revealed a submembranous colocalization of PTP-BL and RIL in epithelial cells. Remarkably, there is also an N-terminal PDZ motif in RIL itself that can bind to the RIL-LIM domain. We demonstrate here that the RIL-LIM domain can be phosphorylated on tyrosine in vitro and in vivo and can be dephosphorylated in vitro by the PTPase domain of PTP-BL. Our data point to the presence of a double PDZ-binding interface on the RIL-LIM domain and suggest tyrosine phosphorylation as a regulatory mechanism for LIM-PDZ associations in the assembly of multiprotein complexes. These findings are in line with an important role of PDZ-mediated interactions in the shaping and organization of submembranous microenvironments of polarized cells.

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13

SCHMEICHEL, Karen L., and Mary C. BECKERLE. "LIM domains of cysteine-rich protein 1 (CRP1) are essential for its zyxin-binding function." Biochemical Journal 331, no. 3 (May 1, 1998): 885–92. http://dx.doi.org/10.1042/bj3310885.

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Previous studies have demonstrated that the adhesion-plaque protein, zyxin, interacts specifically with a 23 kDa protein, called the cysteine-rich protein 1 (CRP1), which has been implicated in myogenesis. Primary sequence analyses have revealed that both zyxin and CRP1 exhibit multiple copies of a structural motif called the LIM domain. LIM domains, which are defined by the consensus CX2CX16–23HX2CX2CX2CX16–23CX2–3(C,H,D), are found in a variety of proteins that are involved in cell growth and differentiation. Recent studies have established that LIM domains are zinc-binding structures that mediate specific protein–protein interactions. For example, in the case of the zyxin–CRP1 interaction, one of zyxin's three LIM domains is necessary and sufficient for binding to CRP1. Because the CRP1 molecule is comprised primarily of two LIM domains, we were interested in the possibility that the binding site for zyxin on CRP1 might also be contained within a single LIM domain. Consistent with the hypothesis that the LIM domains of CRP1 are critical for the protein's zyxin-binding function, zinc-depleted CRP1 displays a reduced zyxin-binding activity. However, domain mapping analyses have revealed that neither of the two individual LIM domains of CRP1 can support a wild-type interaction with zyxin. Collectively, our results suggest that the binding site for zyxin on CRP1 is not contained within a single contiguous sequence of amino acids. Instead, the interaction appears to rely on the co-ordinate action of a number of residues that are displayed in both of CRP1's LIM domains.

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14

Qadota, Hiroshi, Kristina B. Mercer, Rachel K. Miller, Kozo Kaibuchi, and Guy M. Benian. "Two LIM Domain Proteins and UNC-96 Link UNC-97/PINCH to Myosin Thick Filaments in Caenorhabditis elegans Muscle." Molecular Biology of the Cell 18, no. 11 (November 2007): 4317–26. http://dx.doi.org/10.1091/mbc.e07-03-0278.

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By yeast two-hybrid screening, we found three novel interactors (UNC-95, LIM-8, and LIM-9) for UNC-97/PINCH in Caenorhabditis elegans. All three proteins contain LIM domains that are required for binding. Among the three interactors, LIM-8 and LIM-9 also bind to UNC-96, a component of sarcomeric M-lines. UNC-96 and LIM-8 also bind to the C-terminal portion of a myosin heavy chain (MHC), MHC A, which resides in the middle of thick filaments in the proximity of M-lines. All interactions identified by yeast two-hybrid assays were confirmed by in vitro binding assays using purified proteins. All three novel UNC-97 interactors are expressed in body wall muscle and by antibodies localize to M-lines. Either a decreased or an increased dosage of UNC-96 results in disorganization of thick filaments. Our previous studies showed that UNC-98, a C2H2 Zn finger protein, acts as a linkage between UNC-97, an integrin-associated protein, and MHC A in myosin thick filaments. In this study, we demonstrate another mechanism by which this linkage occurs: from UNC-97 through LIM-8 or LIM-9/UNC-96 to myosin.

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15

Stronach, B. E., S. E. Siegrist, and M. C. Beckerle. "Two muscle-specific LIM proteins in Drosophila." Journal of Cell Biology 134, no. 5 (September 1, 1996): 1179–95. http://dx.doi.org/10.1083/jcb.134.5.1179.

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The LIM domain defines a zinc-binding motif found in a growing number of eukaryotic proteins that regulate cell growth and differentiation during development. Members of the cysteine-rich protein (CRP) family of LIM proteins have been implicated in muscle differentiation in vertebrates. Here we report the identification and characterization of cDNA clones encoding two members of the CRP family in Drosophila, referred to as muscle LIM proteins (Mlp). Mlp60A encodes a protein with a single LIM domain linked to a glycine-rich region. Mlp84B encodes a protein with five tandem LIM-glycine modules. In the embryo, Mlp gene expression is spatially restricted to somatic, visceral, and pharyngeal muscles. Within the somatic musculature, Mlp84B transcripts are enriched at the terminal ends of muscle fibers, whereas Mlp60A transcripts are found throughout the muscle fibers. The distributions of the Mlp60A and Mlp84B proteins mirror their respective mRNA localizations, with Mlp84B enrichment occurring at sites of muscle attachment. Northern blot analysis revealed that Mlp gene expression is developmentally regulated, showing a biphasic pattern over the course of the Drosophila life cycle. Peaks of expression occur late in embryogenesis and during metamorphosis, when the musculature is differentiating. Drosophila Mlp60A and Mlp84B, like vertebrate members of the CRP family, have the ability to associate with the actin cytoskeleton when expressed in rat fibroblast cells. The temporal expression and spatial distribution of muscle LIM proteins in Drosophila are consistent with a role for Mlps in myogenesis, late in the differentiation pathway.

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Breen, Joseph J., Alan D. Agulnick, Heiner Westphal, and Igor B. Dawid. "Interactions between LIM Domains and the LIM Domain-binding Protein Ldb1." Journal of Biological Chemistry 273, no. 8 (February 20, 1998): 4712–17. http://dx.doi.org/10.1074/jbc.273.8.4712.

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17

Li, Bo, Lei Zhuang, and Beat Trueb. "Zyxin Interacts with the SH3 Domains of the Cytoskeletal Proteins LIM-nebulette and Lasp-1." Journal of Biological Chemistry 279, no. 19 (March 5, 2004): 20401–10. http://dx.doi.org/10.1074/jbc.m310304200.

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Zyxin is a versatile component of focal adhesions in eukaryotic cells. Here we describe a novel binding partner of zyxin, which we have named LIM-nebulette. LIM-nebulette is an alternative splice variant of the sarcomeric protein nebulette, which, in contrast to nebulette, is expressed in non-muscle cells. It displays a modular structure with an N-terminal LIM domain, three nebulin-like repeats, and a C-terminal SH3 domain and shows high similarity to another cytoskeletal protein, Lasp-1 (LIM and SH3 protein-1). Co-precipitation studies and results obtained with the two-hybrid system demonstrate that LIM-nebulette and Lasp-1 interact specifically with zyxin. Moreover, the SH3 domain from LIM-nebulette is both necessary and sufficient for zyxin binding. The SH3 domains from Lasp-1 and nebulin can also interact with zyxin, but the SH3 domains from more distantly related proteins such as vinexin and sorting nexin 9 do not. On the other hand, the binding site in zyxin is situated at the extreme N terminus as shown by site-directed mutagenesis. LIM-nebulette and Lasp-1 use the same linear binding motif. This motif shows some similarity to a class II binding site but does not contain the classical PXXP sequence. LIM-nebulette reveals a subcellular distribution at focal adhesions similar to Lasp-1. Thus, LIM-nebulette, Lasp-1, and zyxin may play an important role in the organization of focal adhesions.

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18

Thomas, Clément, Flora Moreau, Monika Dieterle, Céline Hoffmann, Sabrina Gatti, Christina Hofmann, Marleen Van Troys, Christophe Ampe, and André Steinmetz. "The LIM Domains of WLIM1 Define a New Class of Actin Bundling Modules." Journal of Biological Chemistry 282, no. 46 (September 7, 2007): 33599–608. http://dx.doi.org/10.1074/jbc.m703691200.

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Actin filament bundling, i.e. the formation of actin cables, is an important process that relies on proteins able to directly bind and cross-link subunits of adjacent actin filaments. Animal cysteine-rich proteins and their plant counterparts are two LIM domain-containing proteins that were recently suggested to define a new family of actin cytoskeleton regulators involved in actin filament bundling. We here identified the LIM domains as responsible for F-actin binding and bundling activities of the tobacco WLIM1. The deletion of one of the two LIM domains reduced significantly, but did not entirely abolish, the ability of WLIM1 to bind actin filaments. Individual LIM domains were found to interact directly with actin filaments, although with a reduced affinity compared with the native protein. Variants lacking the C-terminal or the inter-LIM domain were only weakly affected in their F-actin stabilizing and bundling activities and trigger the formation of thick cables containing tightly packed actin filaments as does the native protein. In contrast, the deletion of one of the two LIM domains negatively impacted both activities and resulted in the formation of thinner and wavier cables. In conclusion, we demonstrate that the LIM domains of WLIM1 are new autonomous actin binding and bundling modules that cooperate to confer WLIM1 high actin binding and bundling activities.

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19

Winkelman, Jonathan D., Caitlin A. Anderson, Cristian Suarez, David R. Kovar, and Margaret L. Gardel. "Evolutionarily diverse LIM domain-containing proteins bind stressed actin filaments through a conserved mechanism." Proceedings of the National Academy of Sciences 117, no. 41 (September 28, 2020): 25532–42. http://dx.doi.org/10.1073/pnas.2004656117.

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The actin cytoskeleton assembles into diverse load-bearing networks, including stress fibers (SFs), muscle sarcomeres, and the cytokinetic ring to both generate and sense mechanical forces. The LIM (Lin11, Isl- 1, and Mec-3) domain family is functionally diverse, but most members can associate with the actin cytoskeleton with apparent force sensitivity. Zyxin rapidly localizes via its LIM domains to failing SFs in cells, known as strain sites, to initiate SF repair and maintain mechanical homeostasis. The mechanism by which these LIM domains associate with stress fiber strain sites (SFSS) is not known. Additionally, it is unknown how widespread strain sensing is within the LIM protein family. We identify that the LIM domain-containing region of 18 proteins from the Zyxin, Paxillin, Tes, and Enigma proteins accumulate to SFSS. Moreover, the LIM domain region from the fission yeast protein paxillin like 1 (Pxl1) also localizes to SFSS in mammalian cells, suggesting that the strain sensing mechanism is ancient and highly conserved. We then used sequence and domain analysis to demonstrate that tandem LIM domains contribute additively, for SFSS localization. Employing in vitro reconstitution, we show that the LIM domain-containing region from mammalian zyxin and fission yeast Pxl1 binds to mechanically stressed F-actin networks but does not associate with relaxed actin filaments. We propose that tandem LIM domains recognize an F-actin conformation that is rare in the relaxed state but is enriched in the presence of mechanical stress.

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Cao, Tingyan, Minghui Qin, Shuai Zhu, and Yuanbao Li. "Silencing of a Cotton Actin-Binding Protein GhWLIM1C Decreases Resistance against Verticillium dahliae Infection." Plants 11, no. 14 (July 12, 2022): 1828. http://dx.doi.org/10.3390/plants11141828.

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LIM proteins are widely spread in various types of plant cells and play diversely crucial cellular roles through actin cytoskeleton assembly and gene expression regulation. Till now, it has not been clear whether LIM proteins function in plant pathogen defense. In this study, we characterized a LIM protein, GhWLIM1C, in upland cotton (Gossypium hirsutum). We found that GhWLIM1C could bind and bundle the actin cytoskeleton, and it contains two LIM domains (LIM1 and LIM2). Both the two domains could bind directly to the actin filaments. Moreover, the LIM2 domain additionally bundles the actin cytoskeleton, indicating that it possesses a different biochemical activity than LIM1. The expression of GhWLIM1C responds to the infection of the cotton fungal pathogen Verticillium dahliae (V. dahliae). Silencing of GhWLIM1C decreased cotton resistance to V. dahliae. These may be associated with the down regulated plant defense response, including the PR genes expression and ROS accumulation in the infected cotton plants. In all, these results provide new evidence that a plant LIM protein functions in plant pathogen resistance and the assembly of the actin cytoskeleton are closely related to the triggering of the plant defense response.

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Chen, Hsiao-Huei, Joseph W. Yip, Alexandre F. R. Stewart, and Eric Frank. "Differential expression of a transcription regulatory factor, the LIM domain only 4 protein Lmo4, in muscle sensory neurons." Development 129, no. 21 (November 1, 2002): 4879–89. http://dx.doi.org/10.1242/dev.129.21.4879.

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In the stretch-reflex system, proprioceptive sensory neurons make selective synaptic connections with different subsets of motoneurons, according to the peripheral muscles they supply. To examine the molecular mechanisms that may influence the selection of these synaptic targets, we constructed single-cell cDNA libraries from sensory neurons that innervate antagonist muscles. Differential screening of these libraries identified a transcription regulatory co-factor of the LIM homeodomain proteins, the LIM domain only 4 protein Lmo4, expressed in most adductor but few sartorius sensory neurons. Differential patterns of Lmo4 expression were also seen in sensory neurons supplying three other muscles. A subset of motoneurons also expresses Lmo4 but the pattern of expression is not specific for motor pools. Differential expression of Lmo4 occurs early, as neurons develop their characteristic LIM homeodomain protein expression patterns. Moreover, ablation of limb buds does not block Lmo4 expression, suggesting that an intrinsic program controls the early differential expression of Lmo4. LIM homeodomain proteins are known to regulate several aspects of sensory and motor neuronal development. Our results suggest that Lmo4 may participate in this differentiation by regulating the transcriptional activity of LIM homeodomain proteins.

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Sadler, I., A. W. Crawford, J. W. Michelsen, and M. C. Beckerle. "Zyxin and cCRP: two interactive LIM domain proteins associated with the cytoskeleton." Journal of Cell Biology 119, no. 6 (December 15, 1992): 1573–87. http://dx.doi.org/10.1083/jcb.119.6.1573.

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Interaction with extracellular matrix can trigger a variety of responses by cells including changes in specific gene expression and cell differentiation. The mechanism by which cell surface events are coupled to the transcriptional machinery is not understood, however, proteins localized at sites of cell-substratum contact are likely to function as signal transducers. We have recently purified and characterized a low abundance adhesion plaque protein called zyxin (Crawford, A. W., and M. C. Beckerle. 1991. J. Biol. Chem. 266:5847-5853; Crawford, A. W., J. W. Michelsen, and M. C. Beckerle. 1992. J. Cell Biol. 116:1381-1393). We have now isolated and sequenced zyxin cDNA and we report here that zyxin exhibits an unusual proline-rich NH2-terminus followed by three tandemly arrayed LIM domains. LIM domains have previously been identified in proteins that play important roles in transcriptional regulation and cellular differentiation. LIM domains have been proposed to coordinate metal ions and we have demonstrated by atomic absorption spectroscopy that purified zyxin binds zinc, a result consistent with the idea that zyxin has zinc fingers. In addition, we have discovered that zyxin interacts in vitro with a 23-kD protein that also exhibits LIM domains. Microsequence analysis has revealed that the 23-kD protein (or cCRP) is the chicken homologue of the human cysteine-rich protein (hCRP). By double-label indirect immunofluorescence, we found that zyxin and cCRP are extensively colocalized in chicken embryo fibroblasts, consistent with the idea that they interact in vivo. We conclude that LIM domains are zinc-binding sequences that may be involved in protein-protein interactions. The demonstration that two cytoskeletal proteins, zyxin and cCRP, share a sequence motif with proteins important for transcriptional regulation raises the possibility that zyxin and cCRP are components of a signal transduction pathway that mediates adhesion-stimulated changes in gene expression.

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Schmeichel, K. L., and M. C. Beckerle. "Molecular dissection of a LIM domain." Molecular Biology of the Cell 8, no. 2 (February 1997): 219–30. http://dx.doi.org/10.1091/mbc.8.2.219.

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LIM domains are novel sequence elements that are found in more than 60 gene products, many of which function as key regulators of developmental pathways. The LIM domain, characterized by the cysteine-rich consensus CX2CX16-23HX2CX2CX2CX16-21 CX2-3(C/H/ D), is a specific mental-binding structure that consists of two distinct zinc-binding subdomains. We and others have recently demonstrated that the LIM domain mediates protein-protein interactions. However, the sequences that define the protein-binding specificity of the LIM domain had not yet been identified. Because structural studies have revealed that the C-terminal zinc-binding module of a LIM domain displays a tertiary fold compatible with nucleic acid binding, it was of interest to determine whether the specific protein-binding activity of a LIM domain could be ascribed to one of its two zinc-binding subdomains. To address this question, we have analyzed the protein-binding capacity of a model LIM peptide, called zLIM1, that is derived from the cytoskeletal protein zyxin. These studies demonstrate that the protein-binding function of zLIM1 can be mapped to sequences contained within its N-terminal zinc-binding module. The C-terminal zinc-binding module of zLIM1 may thus remain accessible to additional interactive partners. Our results raise the possibility that the two structural subdomains of a LIM domain are capable of performing distinct biochemical functions.

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Rauskolb, Cordelia, Ahri Han, Elmira Kirichenko, Consuelo Ibar, and Kenneth D. Irvine. "Analysis of the Drosophila Ajuba LIM protein defines functions for distinct LIM domains." PLOS ONE 17, no. 8 (August 15, 2022): e0269208. http://dx.doi.org/10.1371/journal.pone.0269208.

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The Ajuba LIM protein Jub mediates regulation of Hippo signaling by cytoskeletal tension through interaction with the kinase Warts and participates in feedback regulation of junctional tension through regulation of the cytohesin Steppke. To investigate how Jub interacts with and regulates its distinct partners, we investigated the ability of Jub proteins missing different combinations of its three LIM domains to rescue jub phenotypes and to interact with α-catenin, Warts and Steppke. Multiple regions of Jub contribute to its ability to bind α-catenin and to localize to adherens junctions in Drosophila wing imaginal discs. Co-immunoprecipitation experiments in cultured cells identified a specific requirement for LIM2 for binding to Warts. However, in vivo, both LIM1 and LIM2, but not LIM3, were required for regulation of wing growth, Yorkie activity, and Warts localization. Conversely, LIM2 and LIM3, but not LIM1, were required for regulation of cell shape and Steppke localization in vivo, and for maximal Steppke binding in co-immunoprecipitation experiments. These observations identify distinct functions for the different LIM domains of Jub.

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Li, R. "KBP, a novel protein interacting with LIM protein KyoT." Gene 304 (January 30, 2003): 133–41. http://dx.doi.org/10.1016/s0378-1119(02)01199-x.

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26

te Velthuis, Aartjan J. W., and Christoph P. Bagowski. "PDZ and LIM Domain-Encoding Genes: Molecular Interactions and their Role in Development." Scientific World JOURNAL 7 (2007): 1470–92. http://dx.doi.org/10.1100/tsw.2007.232.

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PDZ/LIM genes encode a group of proteins that play very important, but diverse, biological roles. They have been implicated in numerous vital processes, e.g., cytoskeleton organization, neuronal signaling, cell lineage specification, organ development, and oncogenesis.In mammals, there are ten genes that encode for both a PDZ domain, and one or several LIM domains: four genes of the ALP subfamily (ALP, Elfin, Mystique, and RIL), three of the Enigma subfamily (Enigma, Enigma Homolog, and ZASP), the two LIM kinases (LIMK1 and LIMK2), and the LIM only protein 7 (LMO7). Functionally, all PDZ and LIM domain proteins share an important trait, i.e., they can associate with and/or influence the actin cytoskeleton.We review here the PDZ and LIM domain—encoding genes and their different gene structures, their binding partners, and their role in development and disease. Emphasis is laid on the important questions: why the combination of a PDZ domain with one or more LIM domains is found in such a diverse group of proteins, and what role the PDZ/LIM module could have in signaling complex assembly and localization.Furthermore, the current knowledge on splice form specific expression and the function of these alternative transcripts during vertebrate development will be discussed, since another source of complexity for the PDZ and LIM domain—encoding proteins is introduced by alternative splicing, which often creates different domain combinations.

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Yu, Ting, Xiaofeng Xie, Huixia Wei, Qiuxin Wu, Xiuyan Zhang, Qingmei Tian, Jike Song, and Hongsheng Bi. "Electroacupuncture Improves Choroidal Blood Flow to Inhibit the Development of Lens-Induced Myopia in Guinea Pigs." Evidence-Based Complementary and Alternative Medicine 2022 (June 24, 2022): 1–11. http://dx.doi.org/10.1155/2022/3286583.

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Introduction. The purpose of this paper was to study the effect of electroacupuncture (EA) on choroidal blood flow (ChBF) in a guinea pig model of lens-induced myopia (LIM). Methods. Guinea pigs were randomly divided into 4 groups: normal control (NC) group, LIM group, LIM + electroacupuncture (LIM + EA) group, and LIM + sham acupoint (LIM + sham) group. Right eyes were covered with a −6D lens to induce myopia. Meanwhile, LIM + EA group and LIM + sham group were treated with EA at acupoints Hegu (LI4) and Taiyang (EX-HN5) and sham points. Refraction, axial length (AL), choroidal thickness (ChT), vessel density of choriocapillaris (CC) and choroidal layer, and scleral collagen fiber were measured. Besides, hypoxia-inducible factor-1α (HIF-1α), matrix metalloprotein-2 (MMP-2), and tissue inhibitor metalloprotease-2 (TIMP-2) expression in sclera were detected. Results. Refraction and AL were significantly decreased and ChT and vessel density of CC were significantly increased in LIM + EA group at 2 weeks and 4 weeks (all P < 0.05 ) compared with LIM group. However, no significant difference of vessel density of choroidal layer was observed between LIM and LIM + EA group at 2 weeks and 4 weeks. Scleral collagen fibrils diameters were significantly increased in LIM + EA group at 4 weeks ( P < 0.001 ) compared with LIM group. At the end of experiment, the mRNA and protein expression of HIF-1α and MMP-2 were significantly decreased (all P < 0.05 ) and those of TIMP-2 were increased in LIM + EA, compared with LIM. However, there were no significant differences between LIM and LIM + sham group. Conclusions. EA can improve the vessel density of choroid and then possibly improve scleral hypoxia, which may inhibit the growth of the AL in myopia guinea pig.

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Kanungo, Jyotshnabala, Stephen J. Pratt, Helene Marie, and Gregory D. Longmore. "Ajuba, a Cytosolic LIM Protein, Shuttles into the Nucleus and Affects Embryonal Cell Proliferation and Fate Decisions." Molecular Biology of the Cell 11, no. 10 (October 2000): 3299–313. http://dx.doi.org/10.1091/mbc.11.10.3299.

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Cellular adhesive events affect cell proliferation and differentiation decisions. How cell surface events mediating adhesion transduce signals to the nucleus is not well understood. After cell–cell or cell–substratum contact, cytosolic proteins are recruited to clustered adhesion receptor complexes. One such family of cytosolic proteins found at sites of cell adhesion is the Zyxin family of LIM proteins. Here we demonstrate that the family member Ajuba was recruited to the cell surface of embryonal cells, upon aggregate formation, at sites of cell–cell contact. Ajuba contained a functional nuclear export signal and shuttled into the nucleus. Importantly, accumulation of the LIM domains of Ajuba in the nucleus of P19 embryonal cells resulted in growth inhibition and spontaneous endodermal differentiation. The differentiating effect of Ajuba mapped to the third LIM domain, whereas regulation of proliferation mapped to the first and second LIM domains. Ajuba-induced endodermal differentiation of these cells correlated with the capacity to activate c-Jun kinase and required c-Jun kinase activation. These results suggest that the cytosolic LIM protein Ajuba may provide a new mechanism to transduce signals from sites of cell adhesion to the nucleus, regulating cell growth and differentiation decisions during early development.

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Li, Ya, Shen Liang, Xia Yan, Hong Wang, Debao Li, Darren M. Soanes, Nicholas J. Talbot, Zonghua Wang, and Zhengyi Wang. "Characterization of MoLDB1 Required for Vegetative Growth, Infection-Related Morphogenesis, and Pathogenicity in the Rice Blast Fungus Magnaporthe oryzae." Molecular Plant-Microbe Interactions® 23, no. 10 (October 2010): 1260–74. http://dx.doi.org/10.1094/mpmi-03-10-0052.

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An insertional mutagenesis screen in the rice blast fungus, Magnaporthe oryzae, identified a novel mutant, A2-12-3, which is defective in infection-related morphogenesis and pathogenicity. Analysis of the mutation confirmed an insertion into MoLDB1, which putatively encodes an 806-amino-acid protein with a predicted LIM binding domain. Targeted gene deletion mutants of MoLDB1 were unable to produce asexual or sexual spores and were significantly impaired in vegetative growth and fungal virulence. The Δmoldb1 mutants also showed reduced expression of genes coding hydrophobic proteins (e.g. MPG1 and MHP1), resulting in an easily wettable phenotype in vegetative culture. Moreover, the expression of four genes encoding LIM proteins predicted from the M. oryzae genome was significantly downregulated by deletion of MoLDB1. Analysis of an M. oryzae strain expressing a MoLbd1-green fluorescent protein gene fusion was consistent with the protein being nuclear localized. When considered together, MoLdb1 appears to be involved in regulation of cell wall proteins, including hydrophobins and LIM proteins, and is essential for conidiation, sexual development, appressorium formation, and pathogenicity in M. oryzae.

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Kong, Y., M. J. Flick, A. J. Kudla, and S. F. Konieczny. "Muscle LIM protein promotes myogenesis by enhancing the activity of MyoD." Molecular and Cellular Biology 17, no. 8 (August 1997): 4750–60. http://dx.doi.org/10.1128/mcb.17.8.4750.

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The muscle LIM protein (MLP) is a muscle-specific LIM-only factor that exhibits a dual subcellular localization, being present in both the nucleus and in the cytoplasm. Overexpression of MLP in C2C12 myoblasts enhances skeletal myogenesis, whereas inhibition of MLP activity blocks terminal differentiation. Thus, MLP functions as a positive developmental regulator, although the mechanism through which MLP promotes terminal differentiation events remains unknown. While examining the distinct roles associated with the nuclear and cytoplasmic forms of MLP, we found that nuclear MLP functions through a physical interaction with the muscle basic helix-loop-helix (bHLH) transcription factors MyoD, MRF4, and myogenin. This interaction is highly specific since MLP does not associate with nonmuscle bHLH proteins E12 or E47 or with the myocyte enhancer factor-2 (MEF2) protein, which acts cooperatively with the myogenic bHLH proteins to promote myogenesis. The first LIM motif in MLP and the highly conserved bHLH region of MyoD are responsible for mediating the association between these muscle-specific factors. MLP also interacts with MyoD-E47 heterodimers, leading to an increase in the DNA-binding activity associated with this active bHLH complex. Although MLP lacks a functional transcription activation domain, we propose that it serves as a cofactor for the myogenic bHLH proteins by increasing their interaction with specific DNA regulatory elements. Thus, the functional complex of MLP-MyoD-E protein reveals a novel mechanism for both initiating and maintaining the myogenic program and suggests a global strategy for how LIM-only proteins may control a variety of developmental pathways.

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Toshima, Jiro, Junko Y. Toshima, Toru Amano, Neng Yang, Shuh Narumiya, and Kensaku Mizuno. "Cofilin Phosphorylation by Protein Kinase Testicular Protein Kinase 1 and Its Role in Integrin-mediated Actin Reorganization and Focal Adhesion Formation." Molecular Biology of the Cell 12, no. 4 (April 2001): 1131–45. http://dx.doi.org/10.1091/mbc.12.4.1131.

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Testicular protein kinase 1 (TESK1) is a serine/threonine kinase with a structure composed of a kinase domain related to those of LIM-kinases and a unique C-terminal proline-rich domain. Like LIM-kinases, TESK1 phosphorylated cofilin specifically at Ser-3, both in vitro and in vivo. When expressed in HeLa cells, TESK1 stimulated the formation of actin stress fibers and focal adhesions. In contrast to LIM-kinases, the kinase activity of TESK1 was not enhanced by Rho-associated kinase (ROCK) or p21-activated kinase, indicating that TESK1 is not their downstream effector. Both the kinase activity of TESK1 and the level of cofilin phosphorylation increased by plating cells on fibronectin. Y-27632, a specific inhibitor of ROCK, inhibited LIM-kinase-induced cofilin phosphorylation but did not affect fibronectin-induced or TESK1-induced cofilin phosphorylation in HeLa cells. Expression of a kinase-negative TESK1 suppressed cofilin phosphorylation and formation of stress fibers and focal adhesions induced in cells plated on fibronectin. These results suggest that TESK1 functions downstream of integrins and plays a key role in integrin-mediated actin reorganization, presumably through phosphorylating and inactivating cofilin. We propose that TESK1 and LIM-kinases commonly phosphorylate cofilin but are regulated in different ways and play distinct roles in actin reorganization in living cells.

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Zheng, Bin, Mei Han, and Jin-Kun Wen. "Human heart LIM protein has transcription activation ability related to LIM domain 1." Biochemistry (Moscow) 73, no. 3 (March 2008): 353–57. http://dx.doi.org/10.1134/s0006297908030188.

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Babaeenezhad, Esmaeel, Forouzan Hadipour Moradi, Sobhan Rahimi Monfared, Mohammad Davood Fattahi, Maryam Nasri, Abdolhakim Amini, Omid Dezfoulian та Hassan Ahmadvand. "D-Limonene Alleviates Acute Kidney Injury Following Gentamicin Administration in Rats: Role of NF-κB Pathway, Mitochondrial Apoptosis, Oxidative Stress, and PCNA". Oxidative Medicine and Cellular Longevity 2021 (13 січня 2021): 1–16. http://dx.doi.org/10.1155/2021/6670007.

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Clinical application of gentamicin (GM) is well known to be associated with the development of acute kidney injury (AKI). This study was the first to investigate the possible protective effects of D-limonene (D-lim) on AKI following GM administration in rats. 32 rats arranged in four groups ( n = 8 ): (1) the control group received saline intraperitoneally (0.5 ml/day) and orally (0.5 ml/day), (2) the D-lim group received D-lim (100 mg/kg) orally and saline (0.5 ml/day) intraperitoneally, (3) the GM group received GM (100 mg/kg/day) intraperitoneally and saline (0.5 ml/day) orally, and (4) the treated group received intraperitoneal GM (100 mg/kg) and oral D-lim (100 mg/kg). All treatments were performed daily for 12 consecutive days. Results revealed that D-lim ameliorated GM-induced AKI, oxidative stress, mitochondrial apoptosis, and inflammation. D-lim showed nephroprotective effects as reflected by the decrease in serum urea and creatinine and improvement of renal histopathological changes. D-lim alleviated GM-induced oxidative stress by increasing the activities of renal catalase, serum and renal glutathione peroxidase, and renal superoxide dismutase and decreasing renal malondialdehyde and serum nitric oxide levels. Intriguingly, D-lim suppressed mitochondrial apoptosis by considerably downregulating Bax and caspase-3 (Casp-3) mRNA and protein expressions and markedly enhancing Bcl2 mRNA and protein expressions. Furthermore, D-lim significantly decreases GM-induced inflammatory response through downregulation of NF-κB, IL-6, and TNF-α mRNA and/or protein expressions and decrease in renal myeloperoxidase activity. Finally, D-lim remarkably downregulated PCNA protein expression in the treated group compared with the GM group. In brief, this study showed that D-lim alleviated AKI following GM administration in rats, partially through its antioxidant, anti-inflammatory, and antiapoptotic activities as well as downregulation of PCNA expression.

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Acevedo, Karla, Nathalie Moussi, Rong Li, Priscilla Soo, and Ora Bernard. "LIM Kinase 2 Is Widely Expressed in All Tissues." Journal of Histochemistry & Cytochemistry 54, no. 5 (January 6, 2006): 487–501. http://dx.doi.org/10.1369/jhc.5c6813.2006.

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The LIM kinase family includes two proteins: LIMK1 and LIMK2. These proteins have identical genomic structure and overall amino acid identity of 50%. Both proteins regulate actin polymerization via phosphorylation and inactivation of the actin depolymerizing factors ADF/cofilin. Although the function of endogenous LIMK1 is well established, little is known about the function of the endogenous LIMK2 protein. To understand the specific role of endogenous LIMK2 protein, we examined its expression in embryonic and adult mice using a rat monoclonal antibody, which recognizes specifically the PDZ domain of LIMK2 but not that of LIMK1. Immunoblotting and immunoprecipitation analyses of mouse tissues and human and mouse cell lines revealed widespread expression of the 75-kDa LIMK2 protein. Immunofluorescence analysis demonstrated that the cellular localization of LIMK2 is different from that of LIMK1. LIMK2 protein is found in the cytoplasm localized to punctae and is not enriched within focal adhesions like LIMK1. Immunohistochemical studies revealed that LIMK2 is widely expressed in embryonic and adult mouse tissues and that its expression pattern is similar to that of LIMK1 except in the testes. We have also demonstrated that endogenous LIMK1 and LIMK2 form heterodimers, and that LIMK2 does not always interact with the same proteins as LIMK1. (J Histochem Cytochem 54:487-501, 2006)

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Siddiqui, M., Maulik Badmalia, and Trushar Patel. "Bioinformatic Analysis of Structure and Function of LIM Domains of Human Zyxin Family Proteins." International Journal of Molecular Sciences 22, no. 5 (March 5, 2021): 2647. http://dx.doi.org/10.3390/ijms22052647.

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Members of the human Zyxin family are LIM domain-containing proteins that perform critical cellular functions and are indispensable for cellular integrity. Despite their importance, not much is known about their structure, functions, interactions and dynamics. To provide insights into these, we used a set of in-silico tools and databases and analyzed their amino acid sequence, phylogeny, post-translational modifications, structure-dynamics, molecular interactions, and functions. Our analysis revealed that zyxin members are ohnologs. Presence of a conserved nuclear export signal composed of LxxLxL/LxxxLxL consensus sequence, as well as a possible nuclear localization signal, suggesting that Zyxin family members may have nuclear and cytoplasmic roles. The molecular modeling and structural analysis indicated that Zyxin family LIM domains share similarities with transcriptional regulators and have positively charged electrostatic patches, which may indicate that they have previously unanticipated nucleic acid binding properties. Intrinsic dynamics analysis of Lim domains suggest that only Lim1 has similar internal dynamics properties, unlike Lim2/3. Furthermore, we analyzed protein expression and mutational frequency in various malignancies, as well as mapped protein-protein interaction networks they are involved in. Overall, our comprehensive bioinformatic analysis suggests that these proteins may play important roles in mediating protein-protein and protein-nucleic acid interactions.

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Dawid, Igor B. "LIM protein interactions: Drosophila enters the stage." Trends in Genetics 14, no. 12 (December 1998): 480–82. http://dx.doi.org/10.1016/s0168-9525(98)01615-1.

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Ehsan, Mehroz, Matthew Kelly, Charlotte Hooper, Arash Yavari, Julia Beglov, Mohamed Bellahcene, Kirandeep Ghataorhe, et al. "Mutant Muscle LIM Protein C58G causes cardiomyopathy through protein depletion." Journal of Molecular and Cellular Cardiology 121 (August 2018): 287–96. http://dx.doi.org/10.1016/j.yjmcc.2018.07.248.

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Granger, Anne, Christian Bleux, Marie-Laure Kottler, Simon J. Rhodes, Raymond Counis, and Jean-Noël Laverrière. "The LIM-Homeodomain Proteins Isl-1 and Lhx3 Act with Steroidogenic Factor 1 to Enhance Gonadotrope-Specific Activity of the Gonadotropin-Releasing Hormone Receptor Gene Promoter." Molecular Endocrinology 20, no. 9 (September 1, 2006): 2093–108. http://dx.doi.org/10.1210/me.2005-0184.

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Abstract The GnRH receptor (GnRH-R) plays a central role in mammalian reproductive function throughout adulthood. It also appears as an early marker gene of the presumptive gonadotrope lineage in developing pituitary. Here, using transient transfections combined with DNA/protein interaction assays, we have delineated cis-acting elements within the rat GnRH-R gene promoter that represent targets for the LIM-homeodomain (LIM-HD) proteins, Isl-1 and Lhx3. These factors, critical in early pituitary development, are thus also crucial for gonadotrope-specific expression of the GnRH-R gene. In heterologous cells, the expression of Isl-1 and Lhx3, together with steroidogenic factor 1 (SF-1), culminates in the activation of both the rat as well as human GnRH-R promoter, suggesting that this combination is evolutionarily conserved among mammals. The specificity of these LIM-HD factors is attested by the inefficiency of related proteins, including Lhx5 and Lhx9, to activate the GnRH-R gene promoter, as well as by the repressive capacity of a dominant-negative derivative of Lhx3. Accordingly, targeted deletion of the LIM response element decreases promoter activity. In addition, experiments with Gal4-SF-1 fusion proteins suggest that LIM-HD protein activity in gonadotrope cells is dependent upon SF-1 binding. Finally, using a transgenic model that allows monitoring of in vivo promoter activity, we show that the overlapping expression of Isl-1 and Lhx3 in the developing pituitary correlates with promoter activity. Collectively, these data suggest the occurrence of a specific LIM-HD pituitary code and designate the GnRH-R gene as the first identified transcriptional target of Isl-1 in the anterior pituitary.

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Kuroda, Shun'ichi, Chiharu Tokunaga, Yoshimoto Kiyohara, Osamu Higuchi, Hiroaki Konishi, Kensaku Mizuno, Gordon N. Gill, and Ushio Kikkawa. "Protein-Protein Interaction of Zinc Finger LIM Domains with Protein Kinase C." Journal of Biological Chemistry 271, no. 49 (December 6, 1996): 31029–32. http://dx.doi.org/10.1074/jbc.271.49.31029.

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40

Weiskirchen, Ralf, Josephine D. Pino, Teresita Macalma, Klaus Bister, and Mary C. Beckerle. "The Cysteine-rich Protein Family of Highly Related LIM Domain Proteins." Journal of Biological Chemistry 270, no. 48 (December 1995): 28946–54. http://dx.doi.org/10.1074/jbc.270.48.28946.

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41

Liu, Wei, Jian-Hua Wang, and Mengqing Xiang. "Specific expression of the LIM/Homeodomain protein Lim-1 in horizontal cells during retinogenesis." Developmental Dynamics 217, no. 3 (March 2000): 320–25. http://dx.doi.org/10.1002/(sici)1097-0177(200003)217:3<320::aid-dvdy10>3.0.co;2-f.

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42

Crawford, AW, JD Pino, and MC Beckerle. "Biochemical and molecular characterization of the chicken cysteine-rich protein, a developmentally regulated LIM-domain protein that is associated with the actin cytoskeleton." Journal of Cell Biology 124, no. 1 (January 1, 1994): 117–27. http://dx.doi.org/10.1083/jcb.124.1.117.

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LIM domains are present in a number of proteins including transcription factors, a proto-oncogene product, and the adhesion plaque protein zyxin. The LIM domain exhibits a characteristic arrangement of cysteine and histidine residues and represents a novel zinc binding sequence (Michelsen et al., 1993). Previously, we reported the identification of a 23-kD protein that interacts with zyxin in vitro (Sadler et al., 1992). In this report, we describe the purification and characterization of this 23-kD zyxin-binding protein from avian smooth muscle. Isolation of a cDNA encoding the 23-kD protein has revealed that it consists of 192 amino acids and exhibits two copies of the LIM motif. The 23-kD protein is 91% identical to the human cysteine-rich protein (hCRP); therefore we refer to it as the chicken cysteine-rich protein (cCRP). Examination of a number of chick embryonic tissues by Western immunoblot analysis reveals that cCRP exhibits tissue-specific expression. cCRP is most prominent in tissues that are enriched in smooth muscle cells, such as gizzard, stomach, and intestine. In primary cell cultures derived from embryonic gizzard, differentiated smooth muscle cells exhibit the most striking staining with anti-cCRP antibodies. We have performed quantitative Western immunoblot analysis of cCRP, zyxin, and alpha-actinin levels during embryogenesis. By this approach, we have demonstrated that the expression of cCRP is developmentally regulated.

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43

Turner, C. E., and J. T. Miller. "Primary sequence of paxillin contains putative SH2 and SH3 domain binding motifs and multiple LIM domains: identification of a vinculin and pp125Fak-binding region." Journal of Cell Science 107, no. 6 (June 1, 1994): 1583–91. http://dx.doi.org/10.1242/jcs.107.6.1583.

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Paxillin is a cytoskeletal protein involved in actin-membrane attachment at sites of cell adhesion to the extracellular matrix. Extensive tyrosine phosphorylation of this protein occurs during integrin-mediated cell adhesion, embryonic development, fibroblast transformation and following stimulation of cells by mitogens that operate through the family of seven membrane-spanning G-protein-coupled receptors. Paxillin binds in vitro to the focal adhesion protein vinculin as well as to the SH3 domain of c-src and, when tyrosine phosphorylated, to the SH2 domain of v-crk. Here, we report the complementary DNA, and derived amino acid sequence, that codes for approximately 90% of the paxillin protein. We have identified a region in the amino-terminal half of the protein that supports the binding of both vinculin and the focal adhesion tyrosine kinase, pp125Fak. Although there is no significant overall homology with other identified proteins, the carboxyl third of paxillin contains one LIM domain and three LIM-like sequences. The LIM motif is common to a number of transcription factors and to two other focal adhesion proteins, zyxin and cysteine-rich protein. In addition to several potential tyrosine phosphorylation sites there are five tyrosine-containing sequences that conform to SH2-binding motifs. The protein also contains a short proline-rich region indicative of a SH3-binding domain. Taken together, these data suggest that paxillin is a unique cytoskeletal protein capable of interaction with a variety of intracellular signalling, and structural, molecules important in growth control and the regulation of cytoskeletal organization.(ABSTRACT TRUNCATED AT 250 WORDS)

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44

van Meyel, D. J. "Ssdp proteins bind to LIM-interacting co-factors and regulate the activity of LIM-homeodomain protein complexes in vivo." Development 130, no. 9 (May 1, 2003): 1915–25. http://dx.doi.org/10.1242/dev.00389.

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45

Zheng, Quanhui, and Yong Zhao. "The diverse biofunctions of LIM domain proteins: determined by subcellular localization and protein-protein interaction." Biology of the Cell 99, no. 9 (September 2007): 489–502. http://dx.doi.org/10.1042/bc20060126.

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46

Mils, Valérie, Simon Ming Yuen Lee, Willy Joly, Eric Wong Chi Hang, V. éronique Baldin, Mary Miu Yee Waye, Bernard Ducommun, and Stephen Kwok Wing Tsui. "LIM-only protein FHL3 interacts with CDC25B2 phosphatase." Experimental Cell Research 285, no. 1 (April 15, 2003): 99–106. http://dx.doi.org/10.1016/s0014-4827(03)00018-1.

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47

van Meyel, D. J., D. D. O'Keefe, S. Thor, L. W. Jurata, G. N. Gill, and J. B. Thomas. "Chip is an essential cofactor for apterous in the regulation of axon guidance in Drosophila." Development 127, no. 9 (May 1, 2000): 1823–31. http://dx.doi.org/10.1242/dev.127.9.1823.

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LIM-homeodomain transcription factors are expressed in subsets of neurons and are required for correct axon guidance and neurotransmitter identity. The LIM-homeodomain family member Apterous requires the LIM-binding protein Chip to execute patterned outgrowth of the Drosophila wing. To determine whether Chip is a general cofactor for diverse LIM-homeodomain functions in vivo, we studied its role in the embryonic nervous system. Loss-of-function Chip mutations cause defects in neurotransmitter production that mimic apterous and islet mutants. Chip is also required cell-autonomously by Apterous-expressing neurons for proper axon guidance, and requires both a homodimerization domain and a LIM interaction domain to function appropriately. Using a Chip/Apterous chimeric molecule lacking domains normally required for their interaction, we reconstituted the complex and rescued the axon guidance defects of apterous mutants, of Chip mutants and of embryos doubly mutant for both apterous and Chip. Our results indicate that Chip participates in a range of developmental programs controlled by LIM-homeodomain proteins and that a tetrameric complex comprising two Apterous molecules bridged by a Chip homodimer is the functional unit through which Apterous acts during neuronal differentiation.

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48

Tran, Yen Ha, Zhixiong Xu, Akira Kato, Abinash Chandra Mistry, Yuuki Goya, Masanori Taira, Stephen J. Brandt, and Shigehisa Hirose. "Spliced Isoforms of LIM-Domain-Binding Protein (CLIM/NLI/Ldb) Lacking the LIM-Interaction Domain." Journal of Biochemistry 140, no. 1 (July 1, 2006): 105–19. http://dx.doi.org/10.1093/jb/mvj134.

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49

Shibanuma, Motoko, Kazunori Mori, and Kiyoshi Nose. "HIC-5: A Mobile Molecular Scaffold Regulating the Anchorage Dependence of Cell Growth." International Journal of Cell Biology 2012 (2012): 1–8. http://dx.doi.org/10.1155/2012/426138.

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HIC-5 is a multidomain LIM protein homologous to paxillin that serves as a molecular scaffold at focal adhesions and in the nucleus. It forms mobile molecular units with LIM-only proteins, PINCH, and CRP2 and translocates in and out of the nucleus via a nuclear export signal (NES). Of note, NES of HIC-5 is distinctive in its sensitivity to the cellular redox state. Recently, the mobile units of HIC-5 have been suggested to be involved in the regulation of the anchorage dependence of cell growth. On loss of adhesion, an increase in reactive oxygen species in the cells modifies NES and stops shuttling, which leads to cell-cycle control. More specifically, the system circumvents nuclear localization of cyclin D1 and transactivatesp21Cip1in detached cells, thereby avoiding anchorage-independent cell growth. Thus, the HIC-5-LIM only protein complex has emerged as a fail-safe system for regulating the anchorage dependence of cell growth.

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50

Akazawa, Hiroshi, Sumiyo Kudoh, Naoki Mochizuki, Noboru Takekoshi, Hiroyuki Takano, Toshio Nagai, and Issei Komuro. "A novel LIM protein Cal promotes cardiac differentiation by association with CSX/NKX2-5." Journal of Cell Biology 164, no. 3 (February 2, 2004): 395–405. http://dx.doi.org/10.1083/jcb.200309159.

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The cardiac homeobox transcription factor CSX/NKX2-5 plays an important role in vertebrate heart development. Using a yeast two-hybrid screening, we identified a novel LIM domain–containing protein, named CSX-associated LIM protein (Cal), that interacts with CSX/NKX2-5. CSX/NKX2-5 and Cal associate with each other both in vivo and in vitro, and the LIM domains of Cal and the homeodomain of CSX/NKX2-5 were necessary for mutual binding. Cal itself possessed the transcription-promoting activity, and cotransfection of Cal enhanced CSX/NKX2-5–induced activation of atrial natriuretic peptide gene promoter. Cal contained a functional nuclear export signal and shuttled from the cytoplasm into the nucleus in response to calcium. Accumulation of Cal in the nucleus of P19CL6 cells promoted myocardial cell differentiation accompanied by increased expression levels of the target genes of CSX/NKX2-5. These results suggest that a novel LIM protein Cal induces cardiomyocyte differentiation through its dynamic intracellular shuttling and association with CSX/NKX2-5.

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