Journal articles: 'TIM400'

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Murphy, Michael P., Danielle Leuenberger, Sean P. Curran, Wolfgang Oppliger, and Carla M. Koehler. "The Essential Function of the Small Tim Proteins in the TIM22 Import Pathway Does Not Depend on Formation of the Soluble 70-Kilodalton Complex." Molecular and Cellular Biology 21, no. 18 (September 15, 2001): 6132–38. http://dx.doi.org/10.1128/mcb.21.18.6132-6138.2001.

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ABSTRACT The TIM22 protein import pathway of the yeast mitochondrion contains several components, including a family of five proteins (Tim8p, -9p, -10p, -12p, and -13p [Tim, for translocase of inner membrane]) that are located in the intermembrane space and are 25% identical. Tim9p and Tim10p have dual roles in mediating the import of inner membrane proteins. Like the Tim8p-Tim13p complex, the Tim9p-Tim10p complex functions as a putative chaperone to guide hydrophobic precursors across the intermembrane space. Like membrane-associated Tim12p, they are members of the Tim18p-Tim22p-Tim54p membrane complex that mediates precursor insertion into the membrane. To understand the role of this family in protein import, we have used a genetic approach to manipulate the complement of the small Tim proteins. A strain has been constructed that lacks the 70-kDa soluble Tim8p-Tim13p and Tim9p-Tim10p complexes in the intermembrane space. Instead, a functional version of Tim9p (Tim9S67Cp), identified as a second-site suppressor of a conditional tim10 mutant, maintains viability. Characterization of this strain revealed that Tim9S67Cp and Tim10p were tightly associated with the inner membrane, the soluble 70-kDa Tim8p-Tim13p and Tim9p-Tim10p complexes were not detectable, and the rate of protein import into isolated mitochondria proceeded at a slower rate. An arrested translocation intermediate bound to Tim9S67Cp was located in the intermembrane space, associated with the inner membrane. We suggest that the 70-kDa complexes facilitate import, similar to the outer membrane receptors of the TOM (hetero-oligomeric translocase of the outer membrane) complex, and the essential role of Tim9p and Tim10p may be to mediate protein insertion in the inner membrane with the TIM22 complex.

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Muñoz-Gómez, Sergio A., Shannon N. Snyder, Samantha J. Montoya, and Jeremy G. Wideman. "Independent accretion of TIM22 complex subunits in the animal and fungal lineages." F1000Research 9 (August 28, 2020): 1060. http://dx.doi.org/10.12688/f1000research.25904.1.

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Background: The mitochondrial protein import complexes arose early in eukaryogenesis. Most of the components of the protein import pathways predate the last eukaryotic common ancestor. For example, the carrier-insertase TIM22 complex comprises the widely conserved Tim22 channel core. However, the auxiliary components of fungal and animal TIM22 complexes are exceptions to this ancient conservation. Methods: Using comparative genomics and phylogenetic approaches, we identified precisely when each TIM22 accretion occurred. Results: In animals, we demonstrate that Tim29 and Tim10b arose early in the holozoan lineage. Tim29 predates the metazoan lineage being present in the animal sister lineages, choanoflagellate and filastereans, whereas the erroneously named Tim10b arose from a duplication of Tim9 at the base of metazoans. In fungi, we show that Tim54 has representatives present in every holomycotan lineage including microsporidians and fonticulids, whereas Tim18 and Tim12 appeared much later in fungal evolution. Specifically, Tim18 and Tim12 arose from duplications of Sdh3 and Tim10, respectively, early in the Saccharomycotina. Surprisingly, we show that Tim54 is distantly related to AGK suggesting that AGK and Tim54 are extremely divergent orthologues and the origin of AGK/Tim54 interaction with Tim22 predates the divergence of animals and fungi. Conclusions: We argue that the evolutionary history of the TIM22 complex is best understood as the neutral structural divergence of an otherwise strongly functionally conserved protein complex. This view suggests that many of the differences in structure/subunit composition of multi-protein complexes are non-adaptive. Instead, most of the phylogenetic variation of functionally conserved molecular machines, which have been under stable selective pressures for vast phylogenetic spans, such as the TIM22 complex, is most likely the outcome of the interplay of random genetic drift and mutation pressure.

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Li, Jingzhi, and Bingdong Sha. "The structure of Tim50(164–361) suggests the mechanism by which Tim50 receives mitochondrial presequences." Acta Crystallographica Section F Structural Biology Communications 71, no. 9 (August 25, 2015): 1146–51. http://dx.doi.org/10.1107/s2053230x15013102.

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Mitochondrial preproteins are transported through the translocase of the outer membrane (TOM) complex. Tim50 and Tim23 then transfer preproteins with N-terminal targeting presequences through the intermembrane space (IMS) across the inner membrane. The crystal structure of the IMS domain of Tim50 [Tim50(164–361)] has previously been determined to 1.83 Å resolution. Here, the crystal structure of Tim50(164–361) at 2.67 Å resolution that was crystallized using a different condition is reported. Compared with the previously determined Tim50(164–361) structure, significant conformational changes occur within the protruding β-hairpin of Tim50 and the nearby helix A2. These findings indicate that the IMS domain of Tim50 exhibits significant structural plasticity within the putative presequence-binding groove, which may play important roles in the function of Tim50 as a receptor protein in the TIM complex that interacts with the presequence and multiple other proteins. More interestingly, the crystal packing indicates that helix A1 from the neighboring monomer docks into the putative presequence-binding groove of Tim50(164–361), which may mimic the scenario of Tim50 and the presequence complex. Tim50 may recognize and bind the presequence helix by utilizing the inner side of the protruding β-hairpin through hydrophobic interactions. Therefore, the protruding β-hairpin of Tim50 may play critical roles in receiving the presequence and recruiting Tim23 for subsequent protein translocations.

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Krimmer, Thomas, Joachim Rassow, Wolf-H. Kunau, Wolfgang Voos, and Nikolaus Pfanner. "Mitochondrial Protein Import Motor: the ATPase Domain of Matrix Hsp70 Is Crucial for Binding to Tim44, while the Peptide Binding Domain and the Carboxy-Terminal Segment Play a Stimulatory Role." Molecular and Cellular Biology 20, no. 16 (August 15, 2000): 5879–87. http://dx.doi.org/10.1128/mcb.20.16.5879-5887.2000.

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ABSTRACT The import motor for preproteins that are targeted into the mitochondrial matrix consists of the matrix heat shock protein Hsp70 (mtHsp70) and the translocase subunit Tim44 of the inner membrane. mtHsp70 interacts with Tim44 in an ATP-dependent reaction cycle, binds to preproteins in transit, and drives their translocation into the matrix. While different functional mechanisms are discussed for the mtHsp70-Tim44 machinery, little is known about the actual mode of interaction of both proteins. Here, we have addressed which of the three Hsp70 regions, the ATPase domain, the peptide binding domain, or the carboxy-terminal segment, are required for the interaction with Tim44. By two independent means, a two-hybrid system and coprecipitation of mtHsp70 constructs imported into mitochondria, we show that the ATPase domain interacts with Tim44, although with a reduced efficiency compared to the full-length mtHsp70. The interaction of the ATPase domain with Tim44 is ATP sensitive. The peptide binding domain and carboxy-terminal segment are unable to bind to Tim44 in the absence of the ATPase domain, but both regions enhance the interaction with Tim44 in the presence of the ATPase domain. We conclude that the ATPase domain of mtHsp70 is essential for and directly interacts with Tim44, clearly separating the mtHsp70-Tim44 interaction from the mtHsp70-substrate interaction.

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Merlin, Alessio, Wolfgang Voos, Ammy C. Maarse, Michiel Meijer, Nikolaus Pfanner, and Joachim Rassow. "The J-related Segment of Tim44 Is Essential for Cell Viability: A Mutant Tim44 Remains in the Mitochondrial Import Site, but Inefficiently Recruits mtHsp70 and Impairs Protein Translocation." Journal of Cell Biology 145, no. 5 (May 31, 1999): 961–72. http://dx.doi.org/10.1083/jcb.145.5.961.

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Tim44 is a protein of the mitochondrial inner membrane and serves as an adaptor protein for mtHsp70 that drives the import of preproteins in an ATP-dependent manner. In this study we have modified the interaction of Tim44 with mtHsp70 and characterized the consequences for protein translocation. By deletion of an 18-residue segment of Tim44 with limited similarity to J-proteins, the binding of Tim44 to mtHsp70 was weakened. We found that in the yeast Saccharomyces cerevisiae the deletion of this segment is lethal. To investigate the role of the 18-residue segment, we expressed Tim44Δ18 in addition to the endogenous wild-type Tim44. Tim44Δ18 is correctly targeted to mitochondria and assembles in the inner membrane import site. The coexpression of Tim44Δ18 together with wild-type Tim44, however, does not stimulate protein import, but reduces its efficiency. In particular, the promotion of unfolding of preproteins during translocation is inhibited. mtHsp70 is still able to bind to Tim44Δ18 in an ATP-regulated manner, but the efficiency of interaction is reduced. These results suggest that the J-related segment of Tim44 is needed for productive interaction with mtHsp70. The efficient cooperation of mtHsp70 with Tim44 facilitates the translocation of loosely folded preproteins and plays a crucial role in the import of preproteins which contain a tightly folded domain.

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Mokranjac, Dejana, Martin Sichting, Dušan Popov-Čeleketić, Koyeli Mapa, Lada Gevorkyan-Airapetov, Keren Zohary, Kai Hell, Abdussalam Azem, and Walter Neupert. "Role of Tim50 in the Transfer of Precursor Proteins from the Outer to the Inner Membrane of Mitochondria." Molecular Biology of the Cell 20, no. 5 (March 2009): 1400–1407. http://dx.doi.org/10.1091/mbc.e08-09-0934.

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Transport of essentially all matrix and a number of inner membrane proteins is governed, entirely or in part, by N-terminal presequences and requires a coordinated action of the translocases of outer and inner mitochondrial membranes (TOM and TIM23 complexes). Here, we have analyzed Tim50, a subunit of the TIM23 complex that is implicated in transfer of precursors from TOM to TIM23. Tim50 is recruited to the TIM23 complex via Tim23 in an interaction that is essentially independent of the rest of the translocase. We find Tim50 in close proximity to the intermembrane space side of the TOM complex where it recognizes both types of TIM23 substrates, those that are to be transported into the matrix and those destined to the inner membrane, suggesting that Tim50 recognizes presequences. This function of Tim50 depends on its association with TIM23. We conclude that the efficient transfer of precursors between TOM and TIM23 complexes requires the concerted action of Tim50 with Tim23.

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Schiller, Dirk, Yu Chin Cheng, Qinglian Liu, William Walter, and Elizabeth A. Craig. "Residues of Tim44 Involved in both Association with the Translocon of the Inner Mitochondrial Membrane and Regulation of Mitochondrial Hsp70 Tethering." Molecular and Cellular Biology 28, no. 13 (April 21, 2008): 4424–33. http://dx.doi.org/10.1128/mcb.00007-08.

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ABSTRACT Translocation of proteins from the cytosol across the mitochondrial inner membrane is driven by the action of the import motor, which is associated with the translocon on the matrix side of the membrane. It is well established that an essential peripheral membrane protein, Tim44, tethers mitochondrial Hsp70 (mtHsp70), the core of the import motor, to the translocon. This Tim44-mtHsp70 interaction, which can be recapitulated in vitro, is destabilized by binding of mtHsp70 to a substrate polypeptide. Here we report that the N-terminal 167-amino-acid segment of mature Tim44 is sufficient for both interaction with mtHsp70 and destabilization of a Tim44-mtHsp70 complex caused by client protein binding. Amino acid alterations within a 30-amino-acid segment affected both the release of mtHsp70 upon peptide binding and the interaction of Tim44 with the translocon. Our results support the idea that Tim44 plays multiple roles in mitochondrial protein import by recruiting Ssc1 and its J protein cochaperone to the translocon and coordinating their interactions to promote efficient protein translocation in vivo.

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Davis, Alison J., Naresh B. Sepuri, Jason Holder, Arthur E. Johnson, and Robert E. Jensen. "Two Intermembrane Space Tim Complexes Interact with Different Domains of Tim23p during Its Import into Mitochondria." Journal of Cell Biology 150, no. 6 (September 18, 2000): 1271–82. http://dx.doi.org/10.1083/jcb.150.6.1271.

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Tim23p (translocase of the inner membrane) is an essential import component located in the mitochondrial inner membrane. To determine how the Tim23 protein itself is transported into mitochondria, we used chemical cross-linking to identify proteins adjacent to Tim23p during its biogenesis. In the absence of an inner membrane potential, Tim23p is translocated across the mitochondrial outer membrane, but not inserted into the inner membrane. At this intermediate stage, we find that Tim23p forms cross-linked products with two distinct protein complexes of the intermembrane space, Tim8p–Tim13p and Tim9p–Tim10p. Tim9p and Tim10p cross-link to the COOH-terminal domain of the Tim23 protein, which carries all of the targeting signals for Tim23p. Therefore, our results suggest that the Tim9p–Tim10p complex plays a key role in Tim23p import. In contrast, Tim8p and Tim13p cross-link to the hydrophilic NH2-terminal segment of Tim23p, which does not carry essential import information and, thus, the role of Tim8p–Tim13p is unclear. Tim23p contains two matrix-facing, positively charged loops that are essential for its insertion into the inner membrane. The positive charges are not required for interaction with the Tim9p–Tim10p complex, but are essential for cross-linking of Tim23p to components of the inner membrane insertion machinery, including Tim54p, Tim22p, and Tim12p.

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Baker, Michael J., Chaille T. Webb, David A. Stroud, Catherine S. Palmer, Ann E. Frazier, Bernard Guiard, Agnieszka Chacinska, Jacqueline M. Gulbis, and Michael T. Ryan. "Structural and Functional Requirements for Activity of the Tim9–Tim10 Complex in Mitochondrial Protein Import." Molecular Biology of the Cell 20, no. 3 (February 2009): 769–79. http://dx.doi.org/10.1091/mbc.e08-09-0903.

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The Tim9–Tim10 complex plays an essential role in mitochondrial protein import by chaperoning select hydrophobic precursor proteins across the intermembrane space. How the complex interacts with precursors is not clear, although it has been proposed that Tim10 acts in substrate recognition, whereas Tim9 acts in complex stabilization. In this study, we report the structure of the yeast Tim9–Tim10 hexameric assembly determined to 2.5 Å and have performed mutational analysis in yeast to evaluate the specific roles of Tim9 and Tim10. Like the human counterparts, each Tim9 and Tim10 subunit contains a central loop flanked by disulfide bonds that separate two extended N- and C-terminal tentacle-like helices. Buried salt-bridges between highly conserved lysine and glutamate residues connect alternating subunits. Mutation of these residues destabilizes the complex, causes defective import of precursor substrates, and results in yeast growth defects. Truncation analysis revealed that in the absence of the N-terminal region of Tim9, the hexameric complex is no longer able to efficiently trap incoming substrates even though contacts with Tim10 are still made. We conclude that Tim9 plays an important functional role that includes facilitating the initial steps in translocating precursor substrates into the intermembrane space.

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Truscott, Kaye N., Nils Wiedemann, Peter Rehling, Hanne Müller, Chris Meisinger, Nikolaus Pfanner, and Bernard Guiard. "Mitochondrial Import of the ADP/ATP Carrier: the Essential TIM Complex of the Intermembrane Space Is Required for Precursor Release from the TOM Complex." Molecular and Cellular Biology 22, no. 22 (November 15, 2002): 7780–89. http://dx.doi.org/10.1128/mcb.22.22.7780-7789.2002.

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ABSTRACT The mitochondrial intermembrane space contains a protein complex essential for cell viability, the Tim9-Tim10 complex. This complex is required for the import of hydrophobic membrane proteins, such as the ADP/ATP carrier (AAC), into the inner membrane. Different views exist about the role played by the Tim9-Tim10 complex in translocation of the AAC precursor across the outer membrane. For this report we have generated a new tim10 yeast mutant that leads to a strong defect in AAC import into mitochondria. Thereby, for the first time, authentic AAC is stably arrested in the translocase complex of the outer membrane (TOM), as shown by antibody shift blue native electrophoresis. Surprisingly, AAC is still associated with the receptors Tom70 and Tom20 when the function of Tim10 is impaired. The nonessential Tim8-Tim13 complex of the intermembrane space is not involved in the transfer of AAC across the outer membrane. These results define a two-step mechanism for translocation of AAC across the outer membrane. The initial insertion of AAC into the import channel is independent of the function of Tim9-Tim10; however, completion of translocation across the outer membrane, including release from the TOM complex, requires a functional Tim9-Tim10 complex.

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Tamura, Yasushi, Yoshihiro Harada, Takuya Shiota, Koji Yamano, Kazuaki Watanabe, Mihoko Yokota, Hayashi Yamamoto, Hiromi Sesaki, and Toshiya Endo. "Tim23–Tim50 pair coordinates functions of translocators and motor proteins in mitochondrial protein import." Journal of Cell Biology 184, no. 1 (January 12, 2009): 129–41. http://dx.doi.org/10.1083/jcb.200808068.

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Mitochondrial protein traffic requires coordinated operation of protein translocator complexes in the mitochondrial membrane. The TIM23 complex translocates and inserts proteins into the mitochondrial inner membrane. Here we analyze the intermembrane space (IMS) domains of Tim23 and Tim50, which are essential subunits of the TIM23 complex, in these functions. We find that interactions of Tim23 and Tim50 in the IMS facilitate transfer of precursor proteins from the TOM40 complex, a general protein translocator in the outer membrane, to the TIM23 complex. Tim23–Tim50 interactions also facilitate a late step of protein translocation across the inner membrane by promoting motor functions of mitochondrial Hsp70 in the matrix. Therefore, the Tim23–Tim50 pair coordinates the actions of the TOM40 and TIM23 complexes together with motor proteins for mitochondrial protein import.

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Colavecchia, Marco, Loraine N. Christie, Yashpal S. Kanwar, and David A. Hood. "Functional consequences of thyroid hormone-induced changes in the mitochondrial protein import pathway." American Journal of Physiology-Endocrinology and Metabolism 284, no. 1 (January 1, 2003): E29—E35. http://dx.doi.org/10.1152/ajpendo.00294.2002.

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Thyroid hormone [3,5,3′-triiodo-l-thyronine (T3)] induces phenotypic alterations in cardiac mitochondria, in part by influencing protein import and the expression of the import motor mitochondrial heat shock protein (mtHsp70). Here we examined the adaptability of translocases of the inner membrane (Tim) proteins, as well as the outer membrane receptor Tom34, to T3. Administration of T3 to rats for 5 days increased cardiac Tim23 and Tim44 mRNA levels by 55 and 50%, respectively, but had no effect on Tim17. T3 treatment also induced a 45% increase in Tom34 mRNA, with no accompanying changes at the protein level, suggesting regulation at the posttranscriptional level. In H9c2 cardiac cells, Tim17 mRNA was elevated by 114% by 9 days of differentiation, whereas Tim23 and Tim44 declined by 25 and 29%, respectively. To determine the functional consequences of these T3-induced changes, malate dehydrogenase (MDH) import rates were measured in H9c2 cells stably overexpressing Tim44 and mtHsp70, either alone or in combination. MDH import remained unaltered in cells overexpressing Tim44 or in cells overexpressing both Tim44 and mtHsp70. However, when mtHsp70 was overexpressed alone, a 13% ( P < 0.05) increase in MDH import rate was observed. These findings indicate that import machinery components are differentially regulated in response to stimuli that induce mitochondrial biogenesis, like T3 and differentiation. In addition, the induction of an import machinery component in response to T3 may not necessarily result in functional changes in protein import during mitochondrial biogenesis. Finally, mtHsp70 may play a regulatory role in the import process that is independent of its interaction with Tim44.

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Hutu, Dana P., Bernard Guiard, Agnieszka Chacinska, Dorothea Becker, Nikolaus Pfanner, Peter Rehling, and Martin van der Laan. "Mitochondrial Protein Import Motor: Differential Role of Tim44 in the Recruitment of Pam17 and J-Complex to the Presequence Translocase." Molecular Biology of the Cell 19, no. 6 (June 2008): 2642–49. http://dx.doi.org/10.1091/mbc.e07-12-1226.

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The presequence translocase of the mitochondrial inner membrane (TIM23 complex) mediates the import of preproteins with amino-terminal presequences. To drive matrix translocation the TIM23 complex recruits the presequence translocase-associated motor (PAM) with the matrix heat shock protein 70 (mtHsp70) as central subunit. Activity and localization of mtHsp70 are regulated by four membrane-associated cochaperones: the adaptor protein Tim44, the stimulatory J-complex Pam18/Pam16, and Pam17. It has been proposed that Tim44 serves as molecular platform to localize mtHsp70 and the J-complex at the TIM23 complex, but it is unknown how Pam17 interacts with the translocase. We generated conditional tim44 yeast mutants and selected a mutant allele, which differentially affects the association of PAM modules with TIM23. In tim44-804 mitochondria, the interaction of the J-complex with the TIM23 complex is impaired, whereas unexpectedly the binding of Pam17 is increased. Pam17 interacts with the channel protein Tim23, revealing a new interaction site between TIM23 and PAM. Thus, the motor PAM is composed of functional modules that bind to different sites of the translocase. We suggest that Tim44 is not simply a scaffold for binding of motor subunits but plays a differential role in the recruitment of PAM modules to the inner membrane translocase.

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Vasiljev, Andreja, Uwe Ahting, Frank E. Nargang, Nancy E. Go, Shukry J. Habib, Christian Kozany, Valérie Panneels, et al. "Reconstituted TOM Core Complex and Tim9/Tim10 Complex of Mitochondria Are Sufficient for Translocation of the ADP/ATP Carrier across Membranes." Molecular Biology of the Cell 15, no. 3 (March 2004): 1445–58. http://dx.doi.org/10.1091/mbc.e03-05-0272.

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Precursor proteins of the solute carrier family and of channel forming Tim components are imported into mitochondria in two main steps. First, they are translocated through the TOM complex in the outer membrane, a process assisted by the Tim9/Tim10 complex. They are passed on to the TIM22 complex, which facilitates their insertion into the inner membrane. In the present study, we have analyzed the function of the Tim9/Tim10 complex in the translocation of substrates across the outer membrane of mitochondria. The purified TOM core complex was reconstituted into lipid vesicles in which purified Tim9/Tim10 complex was entrapped. The precursor of the ADP/ATP carrier (AAC) was found to be translocated across the membrane of such lipid vesicles. Thus, these components are sufficient for translocation of AAC precursor across the outer membrane. Peptide libraries covering various substrate proteins were used to identify segments that are bound by Tim9/Tim10 complex upon translocation through the TOM complex. The patterns of binding sites on the substrate proteins suggest a mechanism by which portions of membrane-spanning segments together with flanking hydrophilic segments are recognized and bound by the Tim9/Tim10 complex as they emerge from the TOM complex into the intermembrane space.

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Schulz, Christian, Oleksandr Lytovchenko, Jonathan Melin, Agnieszka Chacinska, Bernard Guiard, Piotr Neumann, Ralf Ficner, Olaf Jahn, Bernhard Schmidt, and Peter Rehling. "Tim50’s presequence receptor domain is essential for signal driven transport across the TIM23 complex." Journal of Cell Biology 195, no. 4 (November 7, 2011): 643–56. http://dx.doi.org/10.1083/jcb.201105098.

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N-terminal targeting signals (presequences) direct proteins across the TOM complex in the outer mitochondrial membrane and the TIM23 complex in the inner mitochondrial membrane. Presequences provide directionality to the transport process and regulate the transport machineries during translocation. However, surprisingly little is known about how presequence receptors interact with the signals and what role these interactions play during preprotein transport. Here, we identify signal-binding sites of presequence receptors through photo-affinity labeling. Using engineered presequence probes, photo cross-linking sites on mitochondrial proteins were mapped mass spectrometrically, thereby defining a presequence-binding domain of Tim50, a core subunit of the TIM23 complex that is essential for mitochondrial protein import. Our results establish Tim50 as the primary presequence receptor at the inner membrane and show that targeting signals and Tim50 regulate the Tim23 channel in an antagonistic manner.

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Naoé, Mari, Yukimasa Ohwa, Daigo Ishikawa, Chié Ohshima, Shuh-ichi Nishikawa, Hayashi Yamamoto, and Toshiya Endo. "Identification of Tim40 That Mediates Protein Sorting to the Mitochondrial Intermembrane Space." Journal of Biological Chemistry 279, no. 46 (September 13, 2004): 47815–21. http://dx.doi.org/10.1074/jbc.m410272200.

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Flannagan, Ronald S., Johnathan Canton, Wendy Furuya, Michael Glogauer, and Sergio Grinstein. "The phosphatidylserine receptor TIM4 utilizes integrins as coreceptors to effect phagocytosis." Molecular Biology of the Cell 25, no. 9 (May 2014): 1511–22. http://dx.doi.org/10.1091/mbc.e13-04-0212.

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T-cell immunoglobulin mucin protein 4 (TIM4), a phosphatidylserine (PtdSer)-binding receptor, mediates the phagocytosis of apoptotic cells. How TIM4 exerts its function is unclear, and conflicting data have emerged. To define the mode of action of TIM4, we used two distinct but complementary approaches: 1) we compared bone marrow–derived macrophages from wild-type and TIM4−/− mice, and 2) we heterologously expressed TIM4 in epithelioid AD293 cells, which rendered them competent for engulfment of PtdSer-bearing targets. Using these systems, we demonstrate that rather than serving merely as a tether, as proposed earlier by others, TIM4 is an active participant in the phagocytic process. Furthermore, we find that TIM4 operates independently of lactadherin, which had been proposed to act as a bridging molecule. Of interest, TIM4-driven phagocytosis depends on the activation of integrins and involves stimulation of Src-family kinases and focal adhesion kinase, as well as the localized accumulation of phosphatidylinositol 3,4,5-trisphosphate. These mediators promote recruitment of the nucleotide-exchange factor Vav3, which in turn activates small Rho-family GTPases. Gene silencing or ablation experiments demonstrated that RhoA, Rac1, and Rac2 act synergistically to drive the remodeling of actin that underlies phagocytosis. Single-particle detection experiments demonstrated that TIM4 and β1 integrins associate upon receptor clustering. These findings support a model in which TIM4 engages integrins as coreceptors to evoke the signal transduction needed to internalize PtdSer-bearing targets such as apoptotic cells.

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Alcock, Felicity H., J. Günter Grossmann, Ian E. Gentle, Vladimir A. Likić, Trevor Lithgow, and Kostas Tokatlidis. "Conserved substrate binding by chaperones in the bacterial periplasm and the mitochondrial intermembrane space." Biochemical Journal 409, no. 2 (December 21, 2007): 377–87. http://dx.doi.org/10.1042/bj20070877.

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Mitochondria were derived from intracellular bacteria and the mitochondrial intermembrane space is topologically equivalent to the bacterial periplasm. Both compartments contain ATP-independent chaperones involved in the transport of hydrophobic membrane proteins. The mitochondrial TIM (translocase of the mitochondrial inner membrane) 10 complex and the periplasmic chaperone SurA were examined in terms of evolutionary relation, structural similarity, substrate binding specificity and their function in transporting polypeptides for insertion into membranes. The two chaperones are evolutionarily unrelated; structurally, they are also distinct both in their characteristics, as determined by SAXS (small-angle X-ray scattering), and in pairwise structural comparison using the distance matrix alignment (DALILite server). Despite their structural differences, SurA and the TIM10 complex share a common binding specificity in Pepscan assays of substrate proteins. Comprehensive analysis of the binding on a total of 1407 immobilized 13-mer peptides revealed that the TIM10 complex, like SurA, does not bind hydrophobic peptides generally, but that both chaperones display selectivity for peptides rich in aromatic residues and with net positive charge. This common binding specificity was not sufficient for SurA to completely replace TIM10 in yeast cells in vivo. In yeast cells lacking TIM10, when SurA is targeted to the intermembrane space of mitochondria, it binds translocating substrate proteins, but fails to completely transfer the substrate to the translocase in the mitochondrial inner membrane. We suggest that SurA was incapable of presenting substrates effectively to the primitive TOM (translocase of the mitochondrial outer membrane) and TIM complexes in early mitochondria, and was replaced by the more effective small Tim chaperone.

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Huang, Yinghui, Jie Zhou, Shenglin Luo, Yang Wang, Jintao He, Peng Luo, Zelin Chen, et al. "Identification of a fluorescent small-molecule enhancer for therapeutic autophagy in colorectal cancer by targeting mitochondrial protein translocase TIM44." Gut 67, no. 2 (November 14, 2016): 307–19. http://dx.doi.org/10.1136/gutjnl-2016-311909.

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ObjectiveAs the modulation of autophagic processes can be therapeutically beneficial to cancer treatment, the identification of novel autophagic enhancers is highly anticipated. However, current autophagy-inducing anticancer agents exert undesired side effects owing to their non-specific biodistribution in off-target tissues. This study aims to develop a multifunctional agent to integrate cancer targeting, imaging and therapy and to investigate its mechanism.DesignA series of mitochondria-targeting near-infrared (NIR) fluorophores were synthesised, screened and identified for their autophagy-enhancing activity. The optical properties and biological effects were tested both in vitro and in vivo. The underlying mechanism was investigated using inhibitors, small interfering RNA (siRNA), RNA sequencing, mass spectrometry and human samples.ResultsWe have screened and identified a new NIR autophagy-enhancer, IR-58, which exhibits significant tumour-selective killing effects. IR-58 preferentially accumulates in the mitochondria of colorectal cancer (CRC) cells and xenografts, a process that is glycolysis-dependent and organic anion transporter polypeptide-dependent. IR-58 kills tumour cells and induces apoptosis via inducing excessive autophagy, which is mediated through the reactive oxygen species (ROS)-Akt-mammalian target of rapamycin (mTOR) pathway. RNA sequencing, mass spectrometry and siRNA interference studies demonstrate that translocase of inner mitochondrial membrane 44 (TIM44)-superoxide dismutase 2 (SOD2) pathway inhibition is responsible for the excessive ROS, autophagy and apoptosis induced by IR-58. TIM44 expression correlates positively with CRC development and poor prognosis in patients.ConclusionsA novel NIR small-molecule autophagy-enhancer, IR-58, with mitochondria-targeted imaging and therapy capabilities was developed for CRC treatment. Additionally, TIM44 was identified for the first time as a potential oncogene, which plays an important role in autophagy through the TIM44-SOD2-ROS-mTOR pathway.

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Truscott, Kaye N., Wolfgang Voos, Ann E. Frazier, Maria Lind, Yanfeng Li, Andreas Geissler, Jan Dudek, et al. "A J-protein is an essential subunit of the presequence translocase–associated protein import motor of mitochondria." Journal of Cell Biology 163, no. 4 (November 24, 2003): 707–13. http://dx.doi.org/10.1083/jcb.200308004.

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Transport of preproteins into the mitochondrial matrix is mediated by the presequence translocase–associated motor (PAM). Three essential subunits of the motor are known: mitochondrial Hsp70 (mtHsp70); the peripheral membrane protein Tim44; and the nucleotide exchange factor Mge1. We have identified the fourth essential subunit of the PAM, an essential inner membrane protein of 18 kD with a J-domain that stimulates the ATPase activity of mtHsp70. The novel J-protein (encoded by PAM18/YLR008c/TIM14) is required for the interaction of mtHsp70 with Tim44 and protein translocation into the matrix. We conclude that the reaction cycle of the PAM of mitochondria involves an essential J-protein.

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Lair, Alan V., and Mark E. Oxley. "Anisotropic nonlinear diffusion with absorption: existence and extinction." International Journal of Mathematics and Mathematical Sciences 19, no. 3 (1996): 427–34. http://dx.doi.org/10.1155/s0161171296000610.

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The authors prove that the nonlinear parabolic partial differential equation∂u∂t=∑i,j=1n∂2∂xi∂xjφij(u)−f(u)with homogeneous Dirichlet boundary conditions and a nonnegative initial condition has a nonnegative generalized solutionu. They also give necessary and sufficient conditions on the constitutive functionsφijandfwhich ensure the existence of a timet0>0for whichuvanishes for allt≥t0.

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Davis, Alison J., Nathan N. Alder, Robert E. Jensen, and Arthur E. Johnson. "The Tim9p/10p and Tim8p/13p Complexes Bind to Specific Sites on Tim23p during Mitochondrial Protein Import." Molecular Biology of the Cell 18, no. 2 (February 2007): 475–86. http://dx.doi.org/10.1091/mbc.e06-06-0546.

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The import of polytopic membrane proteins into the mitochondrial inner membrane (IM) is facilitated by Tim9p/Tim10p and Tim8p/Tim13p protein complexes in the intermembrane space (IMS). These complexes are proposed to act as chaperones by transporting the hydrophobic IM proteins through the aqueous IMS and preventing their aggregation. To examine the nature of this interaction, Tim23p molecules containing a single photoreactive cross-linking probe were imported into mitochondria in the absence of an IM potential where they associated with small Tim complexes in the IMS. On photolysis and immunoprecipitation, a probe located at a particular Tim23p site (27 different locations were examined) was found to react covalently with, in most cases, only one of the small Tim proteins. Tim8p, Tim9p, Tim10p, and Tim13p were therefore positioned adjacent to specific sites in the Tim23p substrate before its integration into the IM. This specificity of binding to Tim23p strongly suggests that small Tim proteins do not function solely as general chaperones by minimizing the exposure of nonpolar Tim23p surfaces to the aqueous medium, but may also align a folded Tim23p substrate in the proper orientation for delivery and integration into the IM at the TIM22 translocon.

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Callegari, Sylvie, Luis Daniel Cruz-Zaragoza, and Peter Rehling. "From TOM to the TIM23 complex – handing over of a precursor." Biological Chemistry 401, no. 6-7 (May 26, 2020): 709–21. http://dx.doi.org/10.1515/hsz-2020-0101.

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AbstractMitochondrial precursor proteins with amino-terminal presequences are imported via the presequence pathway, utilizing the TIM23 complex for inner membrane translocation. Initially, the precursors pass the outer membrane through the TOM complex and are handed over to the TIM23 complex where they are sorted into the inner membrane or translocated into the matrix. This handover process depends on the receptor proteins at the inner membrane, Tim50 and Tim23, which are critical for efficient import. In this review, we summarize key findings that shaped the current concepts of protein translocation along the presequence import pathway, with a particular focus on the precursor handover process from TOM to the TIM23 complex. In addition, we discuss functions of the human TIM23 pathway and the recently uncovered pathogenic mutations in TIM50.

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Yanagihashi, Yuichi, Katsumori Segawa, Ryota Maeda, Yo-ichi Nabeshima, and Shigekazu Nagata. "Mouse macrophages show different requirements for phosphatidylserine receptor Tim4 in efferocytosis." Proceedings of the National Academy of Sciences 114, no. 33 (August 2, 2017): 8800–8805. http://dx.doi.org/10.1073/pnas.1705365114.

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Protein S (ProS) and growth arrest-specific 6 (Gas6) bind to phosphatidylserine (PtdSer) and induce efferocytosis upon binding TAM-family receptors (Tyro3, Axl, and Mer). Here, we produced mouse ProS, Gas6, and TAM-receptor extracellular region fused to IgG fragment crystallizable region in HEK293T cells. ProS and Gas6 bound Ca2+ dependently to PtdSer (Kd 20–40 nM), Mer, and Tyro3 (Kd 15–50 nM). Gas6 bound Axl strongly (Kd < 1.0 nM), but ProS did not bind Axl. Using NIH 3T3-based cell lines expressing a single TAM receptor, we showed that TAM-mediated efferocytosis was determined by the receptor-binding ability of ProS and Gas6. Tim4 is a membrane protein that strongly binds PtdSer. Tim4 alone did not support efferocytosis, but enhanced TAM-dependent efferocytosis. Resident peritoneal macrophages, Kupffer cells, and CD169+ skin macrophages required Tim4 for TAM-stimulated efferocytosis, whereas efferocytosis by thioglycollate-elicited peritoneal macrophages or primary cultured microglia was TAM dependent, but not Tim4 dependent. These results indicate that TAM and Tim4 collaborate for efficient efferocytosis in certain macrophage populations.

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Koehler, Carla M., Michael P. Murphy, Nikolaus A. Bally, Danielle Leuenberger, Wolfgang Oppliger, Luisita Dolfini, Tina Junne, Gottfried Schatz, and Eran Or. "Tim18p, a New Subunit of the TIM22 Complex That Mediates Insertion of Imported Proteins into the Yeast Mitochondrial Inner Membrane." Molecular and Cellular Biology 20, no. 4 (February 15, 2000): 1187–93. http://dx.doi.org/10.1128/mcb.20.4.1187-1193.2000.

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ABSTRACT Import of carrier proteins from the cytoplasm into the mitochondrial inner membrane of yeast is mediated by a distinct system consisting of two soluble 70-kDa protein complexes in the intermembrane space and a 300-kDa complex in the inner membrane, the TIM22 complex. The TIM22 complex contains the peripheral subunits Tim9p, Tim10p, and Tim12p and the integral membrane subunits Tim22p and Tim54p. We identify here an additional subunit, an 18-kDa integral membrane protein termed Tim18p. This protein is made as a 21.9-kDa precursor which is imported into mitochondria and processed to its mature form. When mitochondria are gently solubilized, Tim18p comigrates with the other subunits of the TIM22 complex on nondenaturing gels and is coimmunoprecipitated with Tim54p and Tim12p. Tim18p does not cofractionate with the TIM23 complex upon immunoprecipitation or nondenaturing gel electrophoresis. Deletion of Tim18p decreases the growth rate of yeast cells by a factor of two and is synthetically lethal with temperature-sensitive mutations in Tim9p or Tim10p. It also impairs the import of several precursor proteins into isolated mitochondria, and lowers the apparent mass of the TIM22 complex. We suggest that Tim18p functions in the assembly and stabilization of the TIM22 complex but does not directly participate in protein insertion into the inner membrane.

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Herndon, Jenny D., Steven M. Claypool, and Carla M. Koehler. "The Taz1p Transacylase Is Imported and Sorted into the Outer Mitochondrial Membrane via a Membrane Anchor Domain." Eukaryotic Cell 12, no. 12 (September 27, 2013): 1600–1608. http://dx.doi.org/10.1128/ec.00237-13.

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ABSTRACT Mutations in the mitochondrial transacylase tafazzin, Taz1p, in Saccharomyces cerevisiae cause Barth syndrome, a disease of defective cardiolipin remodeling. Taz1p is an interfacial membrane protein that localizes to both the outer and inner membranes, lining the intermembrane space. Pathogenic point mutations in Taz1p that alter import and membrane insertion result in accumulation of monolysocardiolipin. In this study, we used yeast as a model to investigate the biogenesis of Taz1p. We show that to achieve this unique topology in mitochondria, Taz1p follows a novel import pathway in which it crosses the outer membrane via the translocase of the outer membrane and then uses the Tim9p-Tim10p complex of the intermembrane space to insert into the mitochondrial outer membrane. Taz1p is then transported to membranes of an intermediate density to reach a location in the inner membrane. Moreover, a pathogenic mutation within the membrane anchor (V224R) alters Taz1p import so that it bypasses the Tim9p-Tim10p complex and interacts with the translocase of the inner membrane, TIM23, to reach the matrix. Critical targeting information for Taz1p resides in the membrane anchor and flanking sequences, which are often mutated in Barth syndrome patients. These studies suggest that altering the mitochondrial import pathway of Taz1p may be important in understanding the molecular basis of Barth syndrome.

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Kawano, S., K. Yamano, M. Naoe, T. Momose, K. Terao, S. i. Nishikawa, N. Watanabe, and T. Endo. "Structural basis of yeast Tim40/Mia40 as an oxidative translocator in the mitochondrial intermembrane space." Proceedings of the National Academy of Sciences 106, no. 34 (August 10, 2009): 14403–7. http://dx.doi.org/10.1073/pnas.0901793106.

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Larburu, Natacha, Christopher J. Adams, Chao-Sheng Chen, Piotr R. Nowak, and Maruf M. U. Ali. "Mechanism of Hsp70 specialized interactions in protein translocation and the unfolded protein response." Open Biology 10, no. 8 (August 2020): 200089. http://dx.doi.org/10.1098/rsob.200089.

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Hsp70 chaperones interact with substrate proteins in a coordinated fashion that is regulated by nucleotides and enhanced by assisting cochaperones. There are numerous homologues and isoforms of Hsp70 that participate in a wide variety of cellular functions. This diversity can facilitate adaption or specialization based on particular biological activity and location within the cell. In this review, we highlight two specialized binding partner proteins, Tim44 and IRE1, that interact with Hsp70 at the membrane in order to serve their respective roles in protein translocation and unfolded protein response signalling. Recent mechanistic data suggest analogy in the way the two Hsp70 homologues (BiP and mtHsp70) can bind and release from IRE1 and Tim44 upon substrate engagement. These shared mechanistic features may underlie how Hsp70 interacts with specialized binding partners and may extend our understanding of the mechanistic repertoire that Hsp70 chaperones possess.

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Josyula, Ratnakar, Zhongmin Jin, Deborah McCombs, Lawrence DeLucas, and Bingdong Sha. "Preliminary crystallographic studies of yeast mitochondrial peripheral membrane protein Tim44p." Acta Crystallographica Section F Structural Biology and Crystallization Communications 62, no. 2 (January 27, 2006): 172–74. http://dx.doi.org/10.1107/s1744309106002053.

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Rahman, Bytul, Shin Kawano, Kaori Yunoki-Esaki, Takahiro Anzai, and Toshiya Endo. "NMR analyses on the interactions of the yeast Tim50 C-terminal region with the presequence and Tim50 core domain." FEBS Letters 588, no. 5 (January 23, 2014): 678–84. http://dx.doi.org/10.1016/j.febslet.2013.12.037.

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Ould Amer, Yasmine, and Etienne Hebert-Chatelain. "Insight into the Interactome of Intramitochondrial PKA Using Biotinylation-Proximity Labeling." International Journal of Molecular Sciences 21, no. 21 (November 5, 2020): 8283. http://dx.doi.org/10.3390/ijms21218283.

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Mitochondria are fully integrated in cell signaling. Reversible phosphorylation is involved in adjusting mitochondrial physiology to the cellular needs. Protein kinase A (PKA) phosphorylates several substrates present at the external surface of mitochondria to maintain cellular homeostasis. However, few targets of PKA located inside the organelle are known. The aim of this work was to characterize the impact and the interactome of PKA located inside mitochondria. Our results show that the overexpression of intramitochondrial PKA decreases cellular respiration and increases superoxide levels. Using proximity-dependent biotinylation, followed by LC-MS/MS analysis and in silico phospho-site prediction, we identified 21 mitochondrial proteins potentially targeted by PKA. We confirmed the interaction of PKA with TIM44 using coimmunoprecipitation and observed that TIM44-S80 is a key residue for the interaction between the protein and the kinase. These findings provide insights into the interactome of intramitochondrial PKA and suggest new potential mechanisms in the regulation of mitochondrial functions.

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VERGNOLLE, Maïlys A. S., Helen SAWNEY, Tina JUNNE, Luisita DOLFINI, and Kostas TOKATLIDIS. "A cryptic matrix targeting signal of the yeast ADP/ATP carrier normally inserted by the TIM22 complex is recognized by the TIM23 machinery." Biochemical Journal 385, no. 1 (December 14, 2004): 173–80. http://dx.doi.org/10.1042/bj20040650.

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The yeast ADP/ATP carrier (AAC) is a mitochondrial protein that is targeted to the inner membrane via the TIM10 and TIM22 translocase complexes. AAC is devoid of a typical mitochondrial targeting signal and its targeting and insertion are thought to be guided by internal amino acid sequences. Here we show that AAC contains a cryptic matrix targeting signal that can target up to two thirds of the N-terminal part of the protein to the matrix. This event is coordinated by the TIM23 translocase and displays all the features of the matrix-targeting pathway. However, in the context of the whole protein, this signal is ‘masked’ and rendered non-functional as the polypeptide is targeted to the inner membrane via the TIM10 and TIM22 translocases. Our data suggest that after crossing the outer membrane the whole polypeptide chain of AAC is necessary to commit the precursor to the TIM22-mediated inner membrane insertion pathway.

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Dagher, Marie-Claire. "TIM10 reconstitutes functional import into mitochondrial inner membrane." Trends in Biochemical Sciences 26, no. 9 (September 2001): 530. http://dx.doi.org/10.1016/s0968-0004(01)01956-9.

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Lu, Hui, Scott Allen, Leanne Wardleworth, Peter Savory, and Kostas Tokatlidis. "Functional TIM10 Chaperone Assembly Is Redox-regulatedin Vivo." Journal of Biological Chemistry 279, no. 18 (February 18, 2004): 18952–58. http://dx.doi.org/10.1074/jbc.m313045200.

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Lu, Hui, Alexander P. Golovanov, Felicity Alcock, J. Günter Grossmann, Scott Allen, Lu-Yun Lian, and Kostas Tokatlidis. "The Structural Basis of the TIM10 Chaperone Assembly." Journal of Biological Chemistry 279, no. 18 (February 18, 2004): 18959–66. http://dx.doi.org/10.1074/jbc.m313046200.

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Vergnolle, Mailys A. S., Felicity H. Alcock, Nikos Petrakis, and Kostas Tokatlidis. "Mutation of Conserved Charged Residues in Mitochondrial TIM10 Subunits Precludes TIM10 Complex Assembly, but Does not Abolish Growth of Yeast Cells." Journal of Molecular Biology 371, no. 5 (August 2007): 1315–24. http://dx.doi.org/10.1016/j.jmb.2007.06.025.

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Yamanishi, Yoshinori, Jiro Kitaura, Kumi Izawa, Ayako Kaitani, Yukiko Komeno, Masaki Nakamura, Satoshi Yamazaki, et al. "TIM1 is an endogenous ligand for LMIR5/CD300b: LMIR5 deficiency ameliorates mouse kidney ischemia/reperfusion injury." Journal of Experimental Medicine 207, no. 7 (June 21, 2010): 1501–11. http://dx.doi.org/10.1084/jem.20090581.

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Leukocyte mono-immunoglobulin (Ig)–like receptor 5 (LMIR5)/CD300b is a DAP12-coupled activating receptor predominantly expressed in myeloid cells. The ligands for LMIR have not been reported. We have identified T cell Ig mucin 1 (TIM1) as a possible ligand for LMIR5 by retrovirus-mediated expression cloning. TIM1 interacted only with LMIR5 among the LMIR family, whereas LMIR5 interacted with TIM4 as well as TIM1. The Ig-like domain of LMIR5 bound to TIM1 in the vicinity of the phosphatidylserine (PS)-binding site within the Ig-like domain of TIM1. Unlike its binding to TIM1 or TIM4, LMIR5 failed to bind to PS. LMIR5 binding did not affect TIM1- or TIM4-mediated phagocytosis of apoptotic cells, and stimulation with TIM1 or TIM4 induced LMIR5-mediated activation of mast cells. Notably, LMIR5 deficiency suppressed TIM1-Fc–induced recruitment of neutrophils in the dorsal air pouch, and LMIR5 deficiency attenuated neutrophil accumulation in a model of ischemia/reperfusion injury in the kidneys in which TIM1 expression is up-regulated. In that model, LMIR5 deficiency resulted in ameliorated tubular necrosis and cast formation in the acute phase. Collectively, our results indicate that TIM1 is an endogenous ligand for LMIR5 and that the TIM1–LMIR5 interaction plays a physiological role in immune regulation by myeloid cells.

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Weiss, C., W. Oppliger, G. Vergeres, R. Demel, P. Jeno, M. Horst, B. de Kruijff, G. Schatz, and A. Azem. "Domain structure and lipid interaction of recombinant yeast Tim44." Proceedings of the National Academy of Sciences 96, no. 16 (August 3, 1999): 8890–94. http://dx.doi.org/10.1073/pnas.96.16.8890.

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Vial, Sarah, Hui Lu, Scott Allen, Peter Savory, David Thornton, John Sheehan, and Kostas Tokatlidis. "Assembly of Tim9 and Tim10 into a Functional Chaperone." Journal of Biological Chemistry 277, no. 39 (July 22, 2002): 36100–36108. http://dx.doi.org/10.1074/jbc.m202310200.

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Martincová, Eva, Luboš Voleman, Jan Pyrih, Vojtěch Žárský, Pavlína Vondráčková, Martin Kolísko, Jan Tachezy, and Pavel Doležal. "Probing the Biology of Giardia intestinalis Mitosomes UsingIn VivoEnzymatic Tagging." Molecular and Cellular Biology 35, no. 16 (June 8, 2015): 2864–74. http://dx.doi.org/10.1128/mcb.00448-15.

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Giardia intestinalisparasites contain mitosomes, one of the simplest mitochondrion-related organelles. Strategies to identify the functions of mitosomes have been limited mainly to homology detection, which is not suitable for identifying species-specific proteins and their functions. Anin vivoenzymatic tagging technique based on theEscherichia colibiotin ligase (BirA) has been introduced toG. intestinalis; this method allows for the compartment-specific biotinylation of a protein of interest. Known proteins involved in the mitosomal protein import werein vivotagged, cross-linked, and used to copurify complexes from the outer and inner mitosomal membranes in a single step. New proteins were then identified by mass spectrometry. This approach enabled the identification of highly diverged mitosomal Tim44 (GiTim44), the first known component of the mitosomal inner membrane translocase (TIM). In addition, our subsequent bioinformatics searches returned novel diverged Tim44 paralogs, which mediate the translation and mitosomal insertion of mitochondrially encoded proteins in other eukaryotes. However, most of the identified proteins are specific toG. intestinalisand even absent from the related diplomonad parasiteSpironucleus salmonicida, thus reflecting the unique character of the mitosomal metabolism. Thein vivoenzymatic tagging also showed that proteins enter the mitosome posttranslationally in an unfolded state and without vesicular transport.

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Chaudhuri, Minu, Anuj Tripathi, and Fidel Soto Gonzalez. "Diverse Functions of Tim50, a Component of the Mitochondrial Inner Membrane Protein Translocase." International Journal of Molecular Sciences 22, no. 15 (July 21, 2021): 7779. http://dx.doi.org/10.3390/ijms22157779.

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Mitochondria are essential in eukaryotes. Besides producing 80% of total cellular ATP, mitochondria are involved in various cellular functions such as apoptosis, inflammation, innate immunity, stress tolerance, and Ca2+ homeostasis. Mitochondria are also the site for many critical metabolic pathways and are integrated into the signaling network to maintain cellular homeostasis under stress. Mitochondria require hundreds of proteins to perform all these functions. Since the mitochondrial genome only encodes a handful of proteins, most mitochondrial proteins are imported from the cytosol via receptor/translocase complexes on the mitochondrial outer and inner membranes known as TOMs and TIMs. Many of the subunits of these protein complexes are essential for cell survival in model yeast and other unicellular eukaryotes. Defects in the mitochondrial import machineries are also associated with various metabolic, developmental, and neurodegenerative disorders in multicellular organisms. In addition to their canonical functions, these protein translocases also help maintain mitochondrial structure and dynamics, lipid metabolism, and stress response. This review focuses on the role of Tim50, the receptor component of one of the TIM complexes, in different cellular functions, with an emphasis on the Tim50 homologue in parasitic protozoan Trypanosoma brucei.

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Josyula, Ratnakar, Zhongmin Jin, Zhengqing Fu, and Bingdong Sha. "Crystal Structure of Yeast Mitochondrial Peripheral Membrane Protein Tim44p C-terminal Domain." Journal of Molecular Biology 359, no. 3 (June 2006): 798–804. http://dx.doi.org/10.1016/j.jmb.2006.04.020.

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Rose, Christian. "1 Tim4, 4f. 7.10.2012 Erntedank." Göttinger Predigtmeditationen 66, no. 4 (July 2011): 427–32. http://dx.doi.org/10.13109/gpre.2011.66.4.427.

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Voit, Michael. "Asymptotic distributions for the Ehrenfest urn and related random walks." Journal of Applied Probability 33, no. 02 (June 1996): 340–56. http://dx.doi.org/10.1017/s0021900200099769.

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The distributions of nearest neighbour random walks on hypercubesin continuous timet0 can be expressed in terms of binomial distributions; their limit behaviour fort, N →∞ is well-known. We study here these random walks in discrete time and derive explicit bounds for the deviation of their distribution from their counterparts in continuous time with respect to the total variation norm. Our results lead to a recent asymptotic result of Diaconis, Graham and Morrison for the deviation from uniformity forN →∞.Our proofs use Krawtchouk polynomials and a version of the Diaconis–Shahshahani upper bound lemma. We also apply our methods to certain birth-and-death random walks associated with Krawtchouk polynomials.

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D'Silva, Patrick R., Brenda Schilke, Masaya Hayashi, and Elizabeth A. Craig. "Interaction of the J-Protein Heterodimer Pam18/Pam16 of the Mitochondrial Import Motor with the Translocon of the Inner Membrane." Molecular Biology of the Cell 19, no. 1 (January 2008): 424–32. http://dx.doi.org/10.1091/mbc.e07-08-0748.

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Import of proteins across the inner mitochondrial membrane through the Tim23:Tim17 translocase requires the function of an essential import motor having mitochondrial 70-kDa heat-shock protein (mtHsp70) at its core. The heterodimer composed of Pam18, the J-protein partner of mtHsp70, and the related protein Pam16 is a critical component of this motor. We report that three interactions contribute to association of the heterodimer with the translocon: the N terminus of Pam16 with the matrix side of the translocon, the inner membrane space domain of Pam18 (Pam18IMS) with Tim17, and the direct interaction of the J-domain of Pam18 with the J-like domain of Pam16. Pam16 plays a major role in translocon association, as alterations affecting the stability of the Pam18:Pam16 heterodimer dramatically affect association of Pam18, but not Pam16, with the translocon. Suppressors of the growth defects caused by alterations in the N terminus of Pam16 were isolated and found to be due to mutations in a short segment of TIM44, the gene encoding the peripheral membrane protein that tethers mtHsp70 to the translocon. These data suggest a model in which Tim44 serves as a scaffold for precise positioning of mtHsp70 and its cochaperone Pam18 at the translocon.

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Munawar, Sufian, Ahmer Mehmood, Asif Ali, and Najma Saleem. "Unsteady Boundary-Layer Flow over Jerked Plate Moving in a Free Stream of Viscoelastic Fluid." Scientific World Journal 2014 (2014): 1–7. http://dx.doi.org/10.1155/2014/601950.

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This study aims to investigate the unsteady boundary-layer flow of a viscoelastic non-Newtonian fluid over a flat surface. The plate is suddenly jerked to move with uniform velocity in a uniform stream of non-Newtonian fluid. Purely analytic solution to governing nonlinear equation is obtained. The solution is highly accurate and valid for all values of the dimensionless time0≤τ<∞. Flow properties of the viscoelastic fluid are discussed through graphs.

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Wu, Xiao Bo, Xian Wei Zhou, Shu Ai Du, and Ying Yang. "Modeling and Algorithm of Signal Coverage in Deep Space Communications." Advanced Materials Research 756-759 (September 2013): 3145–48. http://dx.doi.org/10.4028/www.scientific.net/amr.756-759.3145.

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With the increasing demand for deep space exploration, technology of space signal coverage gradually becomes a important research domain in deep space communications. A signal coverage mathematic model was given focused on the characteristics of deep space communications environment especially in celestial body blocking case. An approximation algorithm which used volume measurement in multiple integral is proposed. The approximation algorithm obtained a space covering nodes set based on iteration process in polynomial time0(nm).

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Cui, Wenjun, Ratnakar Josyula, Jingzhi Li, Zhengqing Fu, and Bingdong Sha. "Membrane Binding Mechanism of Yeast Mitochondrial Peripheral Membrane Protzein TIM44." Protein & Peptide Letters 18, no. 7 (July 1, 2011): 718–25. http://dx.doi.org/10.2174/092986611795445996.

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Meinecke, M. "Tim50 Maintains the Permeability Barrier of the Mitochondrial Inner Membrane." Science 312, no. 5779 (June 9, 2006): 1523–26. http://dx.doi.org/10.1126/science.1127628.

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Milenkovic, Dusanka, Kipros Gabriel, Bernard Guiard, Agnes Schulze-Specking, Nikolaus Pfanner, and Agnieszka Chacinska. "Biogenesis of the Essential Tim9–Tim10 Chaperone Complex of Mitochondria." Journal of Biological Chemistry 282, no. 31 (June 6, 2007): 22472–80. http://dx.doi.org/10.1074/jbc.m703294200.

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Journal articles on the topic 'TIM400'

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