Journal articles: 'Protein folding machinery'

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Chiu, Wah. "Center for protein folding machinery." Nanomedicine: Nanotechnology, Biology and Medicine 2, no. 4 (December 2006): 289. http://dx.doi.org/10.1016/j.nano.2006.10.069.

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Zhang, Xiaodong, Fabienne Beuron, and Paul S. Freemont. "Machinery of protein folding and unfolding." Current Opinion in Structural Biology 12, no. 2 (April 2002): 231–38. http://dx.doi.org/10.1016/s0959-440x(02)00315-9.

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Buchner, J. "Introduction: the cellular protein folding machinery." Cellular and Molecular Life Sciences 59, no. 10 (October 2002): 1587–88. http://dx.doi.org/10.1007/pl00012484.

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Fink, Anthony L. "Chaperone-Mediated Protein Folding." Physiological Reviews 79, no. 2 (April 1, 1999): 425–49. http://dx.doi.org/10.1152/physrev.1999.79.2.425.

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The folding of most newly synthesized proteins in the cell requires the interaction of a variety of protein cofactors known as molecular chaperones. These molecules recognize and bind to nascent polypeptide chains and partially folded intermediates of proteins, preventing their aggregation and misfolding. There are several families of chaperones; those most involved in protein folding are the 40-kDa heat shock protein (HSP40; DnaJ), 60-kDa heat shock protein (HSP60; GroEL), and 70-kDa heat shock protein (HSP70; DnaK) families. The availability of high-resolution structures has facilitated a more detailed understanding of the complex chaperone machinery and mechanisms, including the ATP-dependent reaction cycles of the GroEL and HSP70 chaperones. For both of these chaperones, the binding of ATP triggers a critical conformational change leading to release of the bound substrate protein. Whereas the main role of the HSP70/HSP40 chaperone system is to minimize aggregation of newly synthesized proteins, the HSP60 chaperones also facilitate the actual folding process by providing a secluded environment for individual folding molecules and may also promote the unfolding and refolding of misfolded intermediates.

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Rassow, J., K. Mohrs, S. Koidl, I. B. Barthelmess, N. Pfanner, and M. Tropschug. "Cyclophilin 20 is involved in mitochondrial protein folding in cooperation with molecular chaperones Hsp70 and Hsp60." Molecular and Cellular Biology 15, no. 5 (May 1995): 2654–62. http://dx.doi.org/10.1128/mcb.15.5.2654.

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We studied the role of mitochondrial cyclophilin 20 (CyP20), a peptidyl-prolyl cis-trans isomerase, in preprotein translocation across the mitochondrial membranes and protein folding inside the organelle. The inhibitory drug cyclosporin A did not impair membrane translocation of preproteins, but it delayed the folding of an imported protein in wild-type mitochondria. Similarly, Neurospora crassa mitochondria lacking CyP20 efficiently imported preproteins into the matrix, but folding of an imported protein was significantly delayed, indicating that CyP20 is involved in protein folding in the matrix. The slow folding in the mutant mitochondria was not inhibited by cyclosporin A. Folding intermediates of precursor molecules reversibly accumulated at the molecular chaperones Hsp70 and Hsp60 in the matrix. We conclude that CyP20 is a component of the mitochondrial protein folding machinery and that it cooperates with Hsp70 and Hsp60. It is speculated that peptidyl-prolyl cis-trans isomerases in other cellular compartments may similarly promote protein folding in cooperation with chaperone proteins.

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Hartl, F. Ulrich. "Unfolding the chaperone story." Molecular Biology of the Cell 28, no. 22 (November 2017): 2919–23. http://dx.doi.org/10.1091/mbc.e17-07-0480.

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Protein folding in the cell was originally assumed to be a spontaneous process, based on Anfinsen’s discovery that purified proteins can fold on their own after removal from denaturant. Consequently cell biologists showed little interest in the protein folding process. This changed only in the mid and late 1980s, when the chaperone story began to unfold. As a result, we now know that in vivo, protein folding requires assistance by a complex machinery of molecular chaperones. To ensure efficient folding, members of different chaperone classes receive the nascent protein chain emerging from the ribosome and guide it along an ordered pathway toward the native state. I was fortunate to contribute to these developments early on. In this short essay, I will describe some of the critical steps leading to the current concept of protein folding as a highly organized cellular process.

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Sorokina, Irina, Arcady R. Mushegian, and Eugene V. Koonin. "Is Protein Folding a Thermodynamically Unfavorable, Active, Energy-Dependent Process?" International Journal of Molecular Sciences 23, no. 1 (January 4, 2022): 521. http://dx.doi.org/10.3390/ijms23010521.

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The prevailing current view of protein folding is the thermodynamic hypothesis, under which the native folded conformation of a protein corresponds to the global minimum of Gibbs free energy G. We question this concept and show that the empirical evidence behind the thermodynamic hypothesis of folding is far from strong. Furthermore, physical theory-based approaches to the prediction of protein folds and their folding pathways so far have invariably failed except for some very small proteins, despite decades of intensive theory development and the enormous increase of computer power. The recent spectacular successes in protein structure prediction owe to evolutionary modeling of amino acid sequence substitutions enhanced by deep learning methods, but even these breakthroughs provide no information on the protein folding mechanisms and pathways. We discuss an alternative view of protein folding, under which the native state of most proteins does not occupy the global free energy minimum, but rather, a local minimum on a fluctuating free energy landscape. We further argue that ΔG of folding is likely to be positive for the majority of proteins, which therefore fold into their native conformations only through interactions with the energy-dependent molecular machinery of living cells, in particular, the translation system and chaperones. Accordingly, protein folding should be modeled as it occurs in vivo, that is, as a non-equilibrium, active, energy-dependent process.

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Choudhury, P., Y. Liu, and RN Sifers. "Quality Control of Protein Folding: Participation in Human Disease." Physiology 12, no. 4 (August 1, 1997): 162–66. http://dx.doi.org/10.1152/physiologyonline.1997.12.4.162.

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Pedone, Emilia, Danila Limauro, and Simonetta Bartolucci. "The Machinery for Oxidative Protein Folding in Thermophiles." Antioxidants & Redox Signaling 10, no. 1 (January 2008): 157–70. http://dx.doi.org/10.1089/ars.2007.1855.

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Aller, Isabel, and Andreas J. Meyer. "The oxidative protein folding machinery in plant cells." Protoplasma 250, no. 4 (October 23, 2012): 799–816. http://dx.doi.org/10.1007/s00709-012-0463-x.

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Santos, João D., Sara Canato, Ana S. Carvalho, Hugo M. Botelho, Kerman Aloria, Margarida D. Amaral, Rune Matthiesen, Andre O. Falcao, and Carlos M. Farinha. "Folding Status Is Determinant over Traffic-Competence in Defining CFTR Interactors in the Endoplasmic Reticulum." Cells 8, no. 4 (April 14, 2019): 353. http://dx.doi.org/10.3390/cells8040353.

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The most common cystic fibrosis-causing mutation (F508del, present in ~85% of CF patients) leads to CFTR misfolding, which is recognized by the endoplasmic reticulum (ER) quality control (ERQC), resulting in ER retention and early degradation. It is known that CFTR exit from the ER is mediated by specific retention/sorting signals that include four arginine-framed tripeptide (AFT) retention motifs and a diacidic (DAD) exit code that controls the interaction with the COPII machinery. Here, we aim at obtaining a global view of the protein interactors that regulate CFTR exit from the ER. We used mass spectrometry-based interaction proteomics and bioinformatics analyses to identify and characterize proteins interacting with selected CFTR peptide motifs or full-length CFTR variants retained or bypassing these ERQC checkpoints. We conclude that these ERQC trafficking checkpoints rely on fundamental players in the secretory pathway, detecting key components of the protein folding machinery associated with the AFT recognition and of the trafficking machinery recognizing the diacidic code. Furthermore, a greater similarity in terms of interacting proteins is observed for variants sharing the same folding defect over those reaching the same cellular location, evidencing that folding status is dominant over ER escape in shaping the CFTR interactome.

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Alonzi, Dominic S., Kathryn A. Scott, Raymond A. Dwek, and Nicole Zitzmann. "Iminosugar antivirals: the therapeutic sweet spot." Biochemical Society Transactions 45, no. 2 (April 13, 2017): 571–82. http://dx.doi.org/10.1042/bst20160182.

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Many viruses require the host endoplasmic reticulum protein-folding machinery in order to correctly fold one or more of their glycoproteins. Iminosugars with glucose stereochemistry target the glucosidases which are key for entry into the glycoprotein folding cycle. Viral glycoproteins are thus prevented from interacting with the protein-folding machinery leading to misfolding and an antiviral effect against a wide range of different viral families. As iminosugars target host enzymes, they should be refractory to mutations in the virus. Iminosugars therefore have great potential for development as broad-spectrum antiviral therapeutics. We outline the mechanism giving rise to the antiviral activity of iminosugars, the current progress in the development of iminosugar antivirals and future prospects for this field.

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Kang, Ji An, and Young Joo Jeon. "How Is the Fidelity of Proteins Ensured in Terms of Both Quality and Quantity at the Endoplasmic Reticulum? Mechanistic Insights into E3 Ubiquitin Ligases." International Journal of Molecular Sciences 22, no. 4 (February 19, 2021): 2078. http://dx.doi.org/10.3390/ijms22042078.

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The endoplasmic reticulum (ER) is an interconnected organelle that plays fundamental roles in the biosynthesis, folding, stabilization, maturation, and trafficking of secretory and transmembrane proteins. It is the largest organelle and critically modulates nearly all aspects of life. Therefore, in the endoplasmic reticulum, an enormous investment of resources, including chaperones and protein folding facilitators, is dedicated to adequate protein maturation and delivery to final destinations. Unfortunately, the folding and assembly of proteins can be quite error-prone, which leads to the generation of misfolded proteins. Notably, protein homeostasis, referred to as proteostasis, is constantly exposed to danger by flows of misfolded proteins and subsequent protein aggregates. To maintain proteostasis, the ER triages and eliminates terminally misfolded proteins by delivering substrates to the ubiquitin–proteasome system (UPS) or to the lysosome, which is termed ER-associated degradation (ERAD) or ER-phagy, respectively. ERAD not only eliminates misfolded or unassembled proteins via protein quality control but also fine-tunes correctly folded proteins via protein quantity control. Intriguingly, the diversity and distinctive nature of E3 ubiquitin ligases determine efficiency, complexity, and specificity of ubiquitination during ERAD. ER-phagy utilizes the core autophagy machinery and eliminates ERAD-resistant misfolded proteins. Here, we conceptually outline not only ubiquitination machinery but also catalytic mechanisms of E3 ubiquitin ligases. Further, we discuss the mechanistic insights into E3 ubiquitin ligases involved in the two guardian pathways in the ER, ERAD and ER-phagy. Finally, we provide the molecular mechanisms by which ERAD and ER-phagy conduct not only protein quality control but also protein quantity control to ensure proteostasis and subsequent organismal homeostasis.

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Mak, Wai Shun, Tsz Ming Tsang, Tsz Yin Chan, and Georgi L. Lukov. "Novel Binding Partners for CCT and PhLP1 Suggest a Common Folding Mechanism for WD40 Proteins with a 7-Bladed Beta-Propeller Structure." Proteomes 9, no. 4 (October 2, 2021): 40. http://dx.doi.org/10.3390/proteomes9040040.

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This study investigates whether selected WD40 proteins with a 7-bladed β-propeller structure, similar to that of the β subunit of the G protein heterotrimer, interact with the cytosolic chaperonin CCT and its known binding partner, PhLP1. Previous studies have shown that CCT is required for the folding of the Gβ subunit and other WD40 proteins. The role of PhLP1 in the folding of Gβ has also been established, but it is unknown if PhLP1 assists in the folding of other Gβ-like proteins. The binding of three Gβ-like proteins, TBL2, MLST8 and CDC20, to CCT and PhLP1, was demonstrated in this study. Co-immunoprecipitation assays identified one novel binding partner for CCT and three new interactors for PhLP1. All three of the studied proteins interact with CCT and PhLP1, suggesting that these proteins may have a folding machinery in common with that of Gβ and that the well-established Gβ folding mechanism may have significantly broader biological implications than previously thought. These findings contribute to continuous efforts to determine common traits and unique differences in the folding mechanism of the WD40 β-propeller protein family, and the role PhLP1 has in this process.

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Christian Wigley, W., Rosalind P. Fabunmi, Min Goo Lee, Christopher R. Marino, Shmuel Muallem, George N. DeMartino, and Philip J. Thomas. "Dynamic Association of Proteasomal Machinery with the Centrosome." Journal of Cell Biology 145, no. 3 (May 3, 1999): 481–90. http://dx.doi.org/10.1083/jcb.145.3.481.

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Although the number of pathologies known to arise from the inappropriate folding of proteins continues to grow, mechanisms underlying the recognition and ultimate disposition of misfolded polypeptides remain obscure. For example, how and where such substrates are identified and processed is unknown. We report here the identification of a specific subcellular structure in which, under basal conditions, the 20S proteasome, the PA700 and PA28 (700- and 180-kD proteasome activator complexes, respectively), ubiquitin, Hsp70 and Hsp90 (70- and 90-kD heat shock protein, respectively) concentrate in HEK 293 and HeLa cells. The structure is perinuclear, surrounded by endoplasmic reticulum, adjacent to the Golgi, and colocalizes with γ-tubulin, an established centrosomal marker. Density gradient fractions containing purified centrosomes are enriched in proteasomal components and cell stress chaperones. The centrosome-associated structure enlarges in response to inhibition of proteasome activity and the level of misfolded proteins. For example, folding mutants of CFTR form large inclusions which arise from the centrosome upon inhibition of proteasome activity. At high levels of misfolded protein, the structure not only expands but also extensively recruits the cytosolic pools of ubiquitin, Hsp70, PA700, PA28, and the 20S proteasome. Thus, the centrosome may act as a scaffold, which concentrates and recruits the systems which act as censors and modulators of the balance between folding, aggregation, and degradation.

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Meimaridou, Eirini, Sakina B. Gooljar, and J. Paul Chapple. "From hatching to dispatching: the multiple cellular roles of the Hsp70 molecular chaperone machinery." Journal of Molecular Endocrinology 42, no. 1 (October 13, 2008): 1–9. http://dx.doi.org/10.1677/jme-08-0116.

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Molecular chaperones are best recognized for their roles in de novo protein folding and the cellular response to stress. However, many molecular chaperones, and in particular the Hsp70 chaperone machinery, have multiple diverse cellular functions. At the molecular level, chaperones are mediators of protein conformational change. To facilitate conformational change of client/substrate proteins, in manifold contexts, chaperone power must be closely regulated and harnessed to specific cellular locales – this is controlled by cochaperones. This review considers specialized functions of the Hsp70 chaperone machinery mediated by its cochaperones. We focus on vesicular trafficking, protein degradation and a potential role in G protein-coupled receptor processing.

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Roy, Joydeep, Sahana Mitra, Kaushik Sengupta, and Atin K. Mandal. "Hsp70 clears misfolded kinases that partitioned into distinct quality-control compartments." Molecular Biology of the Cell 26, no. 9 (May 2015): 1583–600. http://dx.doi.org/10.1091/mbc.e14-08-1262.

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Hsp70 aids in protein folding and directs misfolded proteins to the cellular degradation machinery. We describe discrete roles of Hsp70,SSA1 as an important quality-control machinery that switches functions to ameliorate the cellular environment. SSA1 facilitates folding/maturation of newly synthesized protein kinases by aiding their phosphorylation process and also stimulates ubiquitylation and degradation of kinases in regular protein turnover or during stress when kinases are denatured or improperly folded. Significantly, while kinases accumulate as insoluble inclusions upon SSA1 inhibition, they form soluble inclusions upon Hsp90 inhibition or stress foci during heat stress. This suggests formation of inclusion-specific quality-control compartments under various stress conditions. Up-regulation of SSA1 results in complete removal of these inclusions by the proteasome. Elevation of the cellular SSA1 level accelerates kinase turnover and protects cells from proteotoxic stress. Upon overexpression, SSA1 targets heat-denatured kinases toward degradation, which could enable them to recover their functional state under physiological conditions. Thus active participation of SSA1 in the degradation of misfolded proteins establishes an essential role of Hsp70 in deciding client fate during stress.

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Hadden, M. Kyle, Lakshmi Galam, Jason E. Gestwicki, Robert L. Matts, and Brian S. J. Blagg. "Derrubone, an Inhibitor of the Hsp90 Protein Folding Machinery." Journal of Natural Products 70, no. 12 (December 2007): 2014–18. http://dx.doi.org/10.1021/np070190s.

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Brownrigg, George P., James Johnson, and Elizabeth J. Rideout. "80 - Sex Differences in β-Cell Protein Folding Machinery." Canadian Journal of Diabetes 44, no. 7 (October 2020): S32. http://dx.doi.org/10.1016/j.jcjd.2020.08.086.

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Chambers, Joseph E., and Stefan J. Marciniak. "Cellular Mechanisms of Endoplasmic Reticulum Stress Signaling in Health and Disease. 2. Protein misfolding and ER stress." American Journal of Physiology-Cell Physiology 307, no. 8 (October 15, 2014): C657—C670. http://dx.doi.org/10.1152/ajpcell.00183.2014.

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The endoplasmic reticulum (ER) is a major site of protein synthesis, most strikingly in the specialized secretory cells of metazoans, which can produce their own weight in proteins daily. Cells possess a diverse machinery to ensure correct folding, assembly, and secretion of proteins from the ER. When this machinery is overwhelmed, the cell is said to experience ER stress, a result of the accumulation of unfolded or misfolded proteins in the lumen of the organelle. Here we discuss the causes of ER stress and the mechanisms by which cells elicit a response, with an emphasis on recent discoveries.

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Zhao, Rongmin, and Walid A. Houry. "Hsp90: a chaperone for protein folding and gene regulation." Biochemistry and Cell Biology 83, no. 6 (December 1, 2005): 703–10. http://dx.doi.org/10.1139/o05-158.

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Molecular chaperones are essential components of a quality control machinery present in the cell. They can either aid in the folding and maintenance of newly translated proteins, or they can lead to the degradation of misfolded and destabilized proteins. Hsp90 is a key member of this machinery. It is a ubiquitous molecular chaperone that is found in eubacteria and all branches of eukarya. It plays a central role in cellular signaling since it is essential for maintaining the activity of several signaling proteins, including steroid hormone receptors and protein kinases. Hsp90 is currently a novel anticancer drug target since it is overexpressed in some cancer cells. The chaperone typically functions as part of large complexes, which include other chaperones and essential cofactors that regulate its function. It is thought that different cofactors target Hsp90 to different sets of substrates. However, the mechanism of Hsp90 function remains poorly understood. As part of an effort to elucidate the Hsp90 chaperone network, we carried out a large-scale proteomics study to identify physical and genetic interactors of the chaperone. We identified 2 highly conserved novel Hsp90 cofactors, termed Tah1 and Pih1, that bind to the chaperone and that also associate physically and functionally with the essential DNA helicases Rvb1 and Rvb2. These helicases are key components of the chromatin remodeling complexes Ino80 and SWR-C. Tah1 and Pih1 seem to represent a novel class of Hsp90 cofactors that allow the chaperone to indirectly affect gene regulation in the cell in addition to its ability to directly promote protein folding. In this review, we provide an overview of Hsp90 structure and function, and we discuss the literature that links the chaperone activity to gene regulation.Key words: Hsp90, chaperone, cochaperone, gene regulation, protein folding.

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Parray, Zahoor Ahmad, Mohammad Shahid, and Asimul Islam. "Insights into Fluctuations of Structure of Proteins: Significance of Intermediary States in Regulating Biological Functions." Polymers 14, no. 8 (April 11, 2022): 1539. http://dx.doi.org/10.3390/polym14081539.

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Proteins are indispensable to cellular communication and metabolism. The structure on which cells and tissues are developed is deciphered from proteins. To perform functions, proteins fold into a three-dimensional structural design, which is specific and fundamentally determined by their characteristic sequence of amino acids. Few of them have structural versatility, allowing them to adapt their shape to the task at hand. The intermediate states appear momentarily, while protein folds from denatured (D) ⇔ native (N), which plays significant roles in cellular functions. Prolific effort needs to be taken in characterizing these intermediate species if detected during the folding process. Protein folds into its native structure through definite pathways, which involve a limited number of transitory intermediates. Intermediates may be essential in protein folding pathways and assembly in some cases, as well as misfolding and aggregation folding pathways. These intermediate states help to understand the machinery of proper folding in proteins. In this review article, we highlight the various intermediate states observed and characterized so far under in vitro conditions. Moreover, the role and significance of intermediates in regulating the biological function of cells are discussed clearly.

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Gandhi, Jason, Anthony C. Antonelli, Adil Afridi, Sohrab Vatsia, Gunjan Joshi, Victor Romanov, Ian V. J. Murray, and Sardar Ali Khan. "Protein misfolding and aggregation in neurodegenerative diseases: a review of pathogeneses, novel detection strategies, and potential therapeutics." Reviews in the Neurosciences 30, no. 4 (May 27, 2019): 339–58. http://dx.doi.org/10.1515/revneuro-2016-0035.

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Abstract Protein folding is a complex, multisystem process characterized by heavy molecular and cellular footprints. Chaperone machinery enables proper protein folding and stable conformation. Other pathways concomitant with the protein folding process include transcription, translation, post-translational modifications, degradation through the ubiquitin-proteasome system, and autophagy. As such, the folding process can go awry in several different ways. The pathogenic basis behind most neurodegenerative diseases is that the disruption of protein homeostasis (i.e. proteostasis) at any level will eventually lead to protein misfolding. Misfolded proteins often aggregate and accumulate to trigger neurotoxicity through cellular stress pathways and consequently cause neurodegenerative diseases. The manifestation of a disease is usually dependent on the specific brain region that the neurotoxicity affects. Neurodegenerative diseases are age-associated, and their incidence is expected to rise as humans continue to live longer and pursue a greater life expectancy. We presently review the sequelae of protein misfolding and aggregation, as well as the role of these phenomena in several neurodegenerative diseases including Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, transmissible spongiform encephalopathies, and spinocerebellar ataxia. Strategies for treatment and therapy are also conferred with respect to impairing, inhibiting, or reversing protein misfolding.

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Scheuner, Donalyn, and Randal J. Kaufman. "The Unfolded Protein Response: A Pathway That Links Insulin Demand with β-Cell Failure and Diabetes." Endocrine Reviews 29, no. 3 (April 24, 2008): 317–33. http://dx.doi.org/10.1210/er.2007-0039.

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Abstract The endoplasmic reticulum (ER) is the entry site into the secretory pathway for newly synthesized proteins destined for the cell surface or released into the extracellular milieu. The study of protein folding and trafficking within the ER is an extremely active area of research that has provided novel insights into many disease processes. Cells have evolved mechanisms to modulate the capacity and quality of the ER protein-folding machinery to prevent the accumulation of unfolded or misfolded proteins. These signaling pathways are collectively termed the unfolded protein response (UPR). The UPR sensors signal a transcriptional response to expand the ER folding capacity, increase degredation of malfolded proteins, and limit the rate of mRNA translation to reduce the client protein load. Recent genetic and biochemical evidence in both humans and mice supports a requirement for the UPR to preserve ER homeostasis and prevent the β-cell failure that may be fundamental in the etiology of diabetes. Chronic or overwhelming ER stress stimuli associated with metabolic syndrome can disrupt protein folding in the ER, reduce insulin secretion, invoke oxidative stress, and activate cell death pathways. Therapeutic interventions to prevent polypeptide-misfolding, oxidative damage, and/or UPR-induced cell death have the potential to improve β-cell function and/or survival in the treatment of diabetes.

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Zhang, Yongli, and Frederick M. Hughson. "Chaperoning SNARE Folding and Assembly." Annual Review of Biochemistry 90, no. 1 (June 20, 2021): 581–603. http://dx.doi.org/10.1146/annurev-biochem-081820-103615.

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SNARE proteins and Sec1/Munc18 (SM) proteins constitute the core molecular engine that drives nearly all intracellular membrane fusion and exocytosis. While SNAREs are known to couple their folding and assembly to membrane fusion, the physiological pathways of SNARE assembly and the mechanistic roles of SM proteins have long been enigmatic. Here, we review recent advances in understanding the SNARE–SM fusion machinery with an emphasis on biochemical and biophysical studies of proteins that mediate synaptic vesicle fusion. We begin by discussing the energetics, pathways, and kinetics of SNARE folding and assembly in vitro. Then, we describe diverse interactions between SM and SNARE proteins and their potential impact on SNARE assembly in vivo. Recent work provides strong support for the idea that SM proteins function as chaperones, their essential role being to enable fast, accurate SNARE assembly. Finally, we review the evidence that SM proteins collaborate with other SNARE chaperones, especially Munc13-1, and briefly discuss some roles of SNARE and SM protein deficiencies in human disease.

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Lim, Shion A., Kathryn M. Hart, Michael J. Harms, and Susan Marqusee. "Evolutionary trend toward kinetic stability in the folding trajectory of RNases H." Proceedings of the National Academy of Sciences 113, no. 46 (October 31, 2016): 13045–50. http://dx.doi.org/10.1073/pnas.1611781113.

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Proper folding of proteins is critical to producing the biological machinery essential for cellular function. The rates and energetics of a protein’s folding process, which is described by its energy landscape, are encoded in the amino acid sequence. Over the course of evolution, this landscape must be maintained such that the protein folds and remains folded over a biologically relevant time scale. How exactly a protein’s energy landscape is maintained or altered throughout evolution is unclear. To study how a protein’s energy landscape changed over time, we characterized the folding trajectories of ancestral proteins of the ribonuclease H (RNase H) family using ancestral sequence reconstruction to access the evolutionary history between RNases H from mesophilic and thermophilic bacteria. We found that despite large sequence divergence, the overall folding pathway is conserved over billions of years of evolution. There are robust trends in the rates of protein folding and unfolding; both modern RNases H evolved to be more kinetically stable than their most recent common ancestor. Finally, our study demonstrates how a partially folded intermediate provides a readily adaptable folding landscape by allowing the independent tuning of kinetics and thermodynamics.

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Shepherd, Colin, Ojore B. V. Oka, and Neil J. Bulleid. "Inactivation of mammalian Ero1α is catalysed by specific protein disulfide-isomerases." Biochemical Journal 461, no. 1 (June 13, 2014): 107–13. http://dx.doi.org/10.1042/bj20140234.

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The formation of disulfides in proteins that enter the endoplasmic reticulum is essential for their folding. We show in the present study that a key component of the machinery for disulfide formation is negatively regulated by the product of its catalytic activity.

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Benham, Adam M., Marcel van Lith, Roberto Sitia, and Ineke Braakman. "Ero1–PDI interactions, the response to redox flux and the implications for disulfide bond formation in the mammalian endoplasmic reticulum." Philosophical Transactions of the Royal Society B: Biological Sciences 368, no. 1617 (May 5, 2013): 20110403. http://dx.doi.org/10.1098/rstb.2011.0403.

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The protein folding machinery of the endoplasmic reticulum (ER) ensures that proteins entering the eukaryotic secretory pathway acquire appropriate post-translational modifications and reach a stably folded state. An important component of this protein folding process is the supply of disulfide bonds. These are introduced into client proteins by ER resident oxidoreductases, including ER oxidoreductin 1 (Ero1). Ero1 is usually considered to function in a linear pathway, by ‘donating’ a disulfide bond to protein disulfide isomerase (PDI) and receiving electrons that are passed on to the terminal electron acceptor molecular oxygen. PDI engages with a range of clients as the direct catalyst of disulfide bond formation, isomerization or reduction. In this paper, we will consider the interactions of Ero1 with PDI family proteins and chaperones, highlighting the effect that redox flux has on Ero1 partnerships. In addition, we will discuss whether higher order protein complexes play a role in Ero1 function.

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Berner, Nicole, Karl-Richard Reutter, and Dieter H. Wolf. "Protein Quality Control of the Endoplasmic Reticulum and Ubiquitin–Proteasome-Triggered Degradation of Aberrant Proteins: Yeast Pioneers the Path." Annual Review of Biochemistry 87, no. 1 (June 20, 2018): 751–82. http://dx.doi.org/10.1146/annurev-biochem-062917-012749.

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Cells must constantly monitor the integrity of their macromolecular constituents. Proteins are the most versatile class of macromolecules but are sensitive to structural alterations. Misfolded or otherwise aberrant protein structures lead to dysfunction and finally aggregation. Their presence is linked to aging and a plethora of severe human diseases. Thus, misfolded proteins have to be rapidly eliminated. Secretory proteins constitute more than one-third of the eukaryotic proteome. They are imported into the endoplasmic reticulum (ER), where they are folded and modified. A highly elaborated machinery controls their folding, recognizes aberrant folding states, and retrotranslocates permanently misfolded proteins from the ER back to the cytosol. In the cytosol, they are degraded by the highly selective ubiquitin–proteasome system. This process of protein quality control followed by proteasomal elimination of the misfolded protein is termed ER-associated degradation (ERAD), and it depends on an intricate interplay between the ER and the cytosol.

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Schlebach, Jonathan P., and Charles R. Sanders. "The safety dance: biophysics of membrane protein folding and misfolding in a cellular context." Quarterly Reviews of Biophysics 48, no. 1 (November 25, 2014): 1–34. http://dx.doi.org/10.1017/s0033583514000110.

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AbstractMost biological processes require the production and degradation of proteins, a task that weighs heavily on the cell. Mutations that compromise the conformational stability of proteins place both specific and general burdens on cellular protein homeostasis (proteostasis) in ways that contribute to numerous diseases. Efforts to elucidate the chain of molecular events responsible for diseases of protein folding address one of the foremost challenges in biomedical science. However, relatively little is known about the processes by which mutations prompt the misfolding of α-helical membrane proteins, which rely on an intricate network of cellular machinery to acquire and maintain their functional structures within cellular membranes. In this review, we summarize the current understanding of the physical principles that guide membrane protein biogenesis and folding in the context of mammalian cells. Additionally, we explore how pathogenic mutations that influence biogenesis may differ from those that disrupt folding and assembly, as well as how this may relate to disease mechanisms and therapeutic intervention. These perspectives indicate an imperative for the use of information from structural, cellular, and biochemical studies of membrane proteins in the design of novel therapeutics and in personalized medicine.

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Hood, David A., and Anna-Maria Joseph. "Mitochondrial assembly: protein import." Proceedings of the Nutrition Society 63, no. 2 (May 2004): 293–300. http://dx.doi.org/10.1079/pns2004342.

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The protein import process of mitochondria is vital for the assembly of the hundreds of nuclear-derived proteins into an expanding organelle reticulum. Most of our knowledge of this complex multisubunit network comes from studies of yeast and fungal systems, with little information known about the protein import process in mammalian cells, particularly skeletal muscle. However, growing evidence indicates that the protein import machinery can respond to changes in the energy status of the cell. In particular, contractile activity, a powerful inducer of mitochondrial biogenesis, has been shown to alter the stoichiometry of the protein import apparatus via changes in several protein import machinery components. These adaptations include the induction of cytosolic molecular chaperones that transport precursors to the matrix, the up-regulation of outer membrane import receptors, and the increase in matrix chaperonins that facilitate the import and proper folding of the protein for subsequent compartmentation in the matrix or inner membrane. The physiological importance of these changes is an increased capacity for import into the organelle at any given precursor concentration. Defects in the protein import machinery components have been associated with mitochondrial disorders. Thus, contractile activity may serve as a possible mechanism for up-regulation of mitochondrial protein import and compensation for mitochondrial phenotype alterations observed in diseased muscle.

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Daverkausen-Fischer, Lea, Margarethe Draga, and Felicitas Pröls. "Regulation of Translation, Translocation, and Degradation of Proteins at the Membrane of the Endoplasmic Reticulum." International Journal of Molecular Sciences 23, no. 10 (May 17, 2022): 5576. http://dx.doi.org/10.3390/ijms23105576.

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The endoplasmic reticulum (ER) of mammalian cells is the central organelle for the maturation and folding of transmembrane proteins and for proteins destined to be secreted into the extracellular space. The proper folding of target proteins is achieved and supervised by a complex endogenous chaperone machinery. BiP, a member of the Hsp70 protein family, is the central chaperone in the ER. The chaperoning activity of BiP is assisted by ER-resident DnaJ (ERdj) proteins due to their ability to stimulate the low, intrinsic ATPase activity of BiP. Besides their co-chaperoning activity, ERdj proteins also regulate and tightly control the translation, translocation, and degradation of proteins. Disturbances in the luminal homeostasis result in the accumulation of unfolded proteins, thereby eliciting a stress response, the so-called unfolded protein response (UPR). Accumulated proteins are either deleterious due to the functional loss of the respective protein and/or due to their deposition as intra- or extracellular protein aggregates. A variety of metabolic diseases are known to date, which are associated with the dysfunction of components of the chaperone machinery. In this review, we will delineate the impact of ERdj proteins in controlling protein synthesis and translocation under physiological and under stress conditions. A second aspect of this review is dedicated to the role of ERdj proteins in the ER-associated degradation pathway, by which unfolded or misfolded proteins are discharged from the ER. We will refer to some of the most prominent diseases known to be based on the dysfunction of ERdj proteins.

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Stubenrauch, Christopher J., Gordon Dougan, Trevor Lithgow, and Eva Heinz. "Constraints on lateral gene transfer in promoting fimbrial usher protein diversity and function." Open Biology 7, no. 11 (November 2017): 170144. http://dx.doi.org/10.1098/rsob.170144.

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Fimbriae are long, adhesive structures widespread throughout members of the family Enterobacteriaceae. They are multimeric extrusions, which are moved out of the bacterial cell through an integral outer membrane protein called usher. The complex folding mechanics of the usher protein were recently revealed to be catalysed by the membrane-embedded translocation and assembly module (TAM). Here, we examine the diversity of usher proteins across a wide range of extraintestinal (ExPEC) and enteropathogenic (EPEC) Escherichia coli , and further focus on a so far undescribed chaperone–usher system, with this usher referred to as UshC. The fimbrial system containing UshC is distributed across a discrete set of EPEC types, including model strains like E2348/67, as well as ExPEC ST131, currently the most prominent multi-drug-resistant uropathogenic E. coli strain worldwide. Deletion of the TAM from a naive strain of E. coli results in a drastic time delay in folding of UshC, which can be observed for a protein from EPEC as well as for two introduced proteins from related organisms, Yersinia and Enterobacter . We suggest that this models why the TAM machinery is essential for efficient folding of proteins acquired via lateral gene transfer.

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Zhu, Lu, H. Ronald Kaback, and Ross E. Dalbey. "YidC Protein, a Molecular Chaperone for LacY Protein Folding via the SecYEG Protein Machinery." Journal of Biological Chemistry 288, no. 39 (August 8, 2013): 28180–94. http://dx.doi.org/10.1074/jbc.m113.491613.

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Shen, Gang, and Brian S. J. Blagg. "Radester, a Novel Inhibitor of the Hsp90 Protein Folding Machinery." Organic Letters 7, no. 11 (May 2005): 2157–60. http://dx.doi.org/10.1021/ol050580a.

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Hamazaki, Jun, and Shigeo Murata. "ER-Resident Transcription Factor Nrf1 Regulates Proteasome Expression and Beyond." International Journal of Molecular Sciences 21, no. 10 (May 23, 2020): 3683. http://dx.doi.org/10.3390/ijms21103683.

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Protein folding is a substantively error prone process, especially when it occurs in the endoplasmic reticulum (ER). The highly exquisite machinery in the ER controls secretory protein folding, recognizes aberrant folding states, and retrotranslocates permanently misfolded proteins from the ER back to the cytosol; these misfolded proteins are then degraded by the ubiquitin–proteasome system termed as the ER-associated degradation (ERAD). The 26S proteasome is a multisubunit protease complex that recognizes and degrades ubiquitinated proteins in an ATP-dependent manner. The complex structure of the 26S proteasome requires exquisite regulation at the transcription, translation, and molecular assembly levels. Nuclear factor erythroid-derived 2-related factor 1 (Nrf1; NFE2L1), an ER-resident transcription factor, has recently been shown to be responsible for the coordinated expression of all the proteasome subunit genes upon proteasome impairment in mammalian cells. In this review, we summarize the current knowledge regarding the transcriptional regulation of the proteasome, as well as recent findings concerning the regulation of Nrf1 transcription activity in ER homeostasis and metabolic processes.

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Pety de Thozée, Cédric, and Michel Ghislain. "ER-Associated Degradation of Membrane Proteins in Yeast." Scientific World JOURNAL 6 (2006): 967–83. http://dx.doi.org/10.1100/tsw.2006.191.

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Proteins destined for the secretory pathway are translocated into the endoplasmic reticulum (ER), where they are subjected to a variety of post-translational modifications before they reach their final destination. Newly synthesized proteins that have defect in polypeptide folding or subunit assembly are recognized by quality control systems and eliminated by the 26S proteasome, a cytosolic ATP-dependent proteolytic machinery. Delivery of non-native ER proteins to the proteasome requires retrograde transport across the ER membrane and depends on a protein-unfolding machine consisting of Cdc48p, Ufd1p, and Npl4p. Recent studies in yeast have highlighted the possible function of the Sar1p/COPII machinery in ER-associated degradation of some lumenal and membrane proteins.

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Yoo, Yoon Seon, Hye Gyeong Han, and Young Joo Jeon. "Unfolded Protein Response of the Endoplasmic Reticulum in Tumor Progression and Immunogenicity." Oxidative Medicine and Cellular Longevity 2017 (December 21, 2017): 1–18. http://dx.doi.org/10.1155/2017/2969271.

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The endoplasmic reticulum (ER) is a pivotal regulator of folding, quality control, trafficking, and targeting of secreted and transmembrane proteins, and accordingly, eukaryotic cells have evolved specialized machinery to ensure that the ER enables these proteins to acquire adequate folding and maturation in the presence of intrinsic and extrinsic insults. This adaptive capacity of the ER to intrinsic and extrinsic perturbations is important for maintaining protein homeostasis, which is termed proteostasis. Failure in adaptation to these perturbations leads to accumulation of misfolded or unassembled proteins in the ER, which is termed ER stress, resulting in the activation of unfolded protein response (UPR) of the ER and the execution of ER-associated degradation (ERAD) to restore homeostasis. Furthermore, both of the two axes play key roles in the control of tumor progression, inflammation, immunity, and aging. Therefore, understanding UPR of the ER and subsequent ERAD will provide new insights into the pathogenesis of many human diseases and contribute to therapeutic intervention in these diseases.

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Latorre, Victor, Florian Mattenberger, and Ron Geller. "Chaperoning the Mononegavirales: Current Knowledge and Future Directions." Viruses 10, no. 12 (December 8, 2018): 699. http://dx.doi.org/10.3390/v10120699.

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The order Mononegavirales harbors numerous viruses of significant relevance to human health, including both established and emerging infections. Currently, vaccines are only available for a small subset of these viruses, and antiviral therapies remain limited. Being obligate cellular parasites, viruses must utilize the cellular machinery for their replication and spread. Therefore, targeting cellular pathways used by viruses can provide novel therapeutic approaches. One of the key challenges confronted by both hosts and viruses alike is the successful folding and maturation of proteins. In cells, this task is faced by cellular molecular chaperones, a group of conserved and abundant proteins that oversee protein folding and help maintain protein homeostasis. In this review, we summarize the current knowledge of how the Mononegavirales interact with cellular chaperones, highlight key gaps in our knowledge, and discuss the potential of chaperone inhibitors as antivirals.

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Voss-Andreae, Julian. "Protein Sculptures: Life's Building Blocks Inspire Art." Leonardo 38, no. 1 (February 2005): 41–45. http://dx.doi.org/10.1162/leon.2005.38.1.41.

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The author takes a literal look at the foundation of our physical existence by creating sculptures of proteins, the universal parts of the machinery of life. For him, it is less important to copy a molecule accurately in all its details than to find a guiding principle and follow it to see whether it yields artistically interesting results. The main idea underlying these sculptures is the analogy between the technique of mitered cuts and protein folding. The sculptures offer a sensual experience of a world that is usually accessible only through the intellect.

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Liu, Yi-Chang, Danica Galonić Fujimori, and Jonathan S. Weissman. "Htm1p–Pdi1p is a folding-sensitive mannosidase that marks N-glycoproteins for ER-associated protein degradation." Proceedings of the National Academy of Sciences 113, no. 28 (June 28, 2016): E4015—E4024. http://dx.doi.org/10.1073/pnas.1608795113.

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Our understanding of how the endoplasmic reticulum (ER)-associated protein degradation (ERAD) machinery efficiently targets terminally misfolded proteins while avoiding the misidentification of nascent polypeptides and correctly folded proteins is limited. For luminal N-glycoproteins, demannosylation of their N-glycan to expose a terminal α1,6-linked mannose is necessary for their degradation via ERAD, but whether this modification is specific to misfolded proteins is unknown. Here we report that the complex of the mannosidase Htm1p and the protein disulfide isomerase Pdi1p (Htm1p–Pdi1p) acts as a folding-sensitive mannosidase for catalyzing this first committed step in Saccharomyces cerevisiae. We reconstitute this step in vitro with Htm1p–Pdi1p and model glycoprotein substrates whose structural states we can manipulate. We find that Htm1p–Pdi1p is a glycoprotein-specific mannosidase that preferentially targets nonnative glycoproteins trapped in partially structured states. As such, Htm1p–Pdi1p is suited to act as a licensing factor that monitors folding in the ER lumen and preferentially commits glycoproteins trapped in partially structured states for degradation.

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Böttinger, Lena, Agnieszka Gornicka, Tomasz Czerwik, Piotr Bragoszewski, Adrianna Loniewska-Lwowska, Agnes Schulze-Specking, Kaye N. Truscott, Bernard Guiard, Dusanka Milenkovic, and Agnieszka Chacinska. "In vivo evidence for cooperation of Mia40 and Erv1 in the oxidation of mitochondrial proteins." Molecular Biology of the Cell 23, no. 20 (October 15, 2012): 3957–69. http://dx.doi.org/10.1091/mbc.e12-05-0358.

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The intermembrane space of mitochondria accommodates the essential mitochondrial intermembrane space assembly (MIA) machinery that catalyzes oxidative folding of proteins. The disulfide bond formation pathway is based on a relay of reactions involving disulfide transfer from the sulfhydryl oxidase Erv1 to Mia40 and from Mia40 to substrate proteins. However, the substrates of the MIA typically contain two disulfide bonds. It was unclear what the mechanisms are that ensure that proteins are released from Mia40 in a fully oxidized form. In this work, we dissect the stage of the oxidative folding relay, in which Mia40 binds to its substrate. We identify dynamics of the Mia40–substrate intermediate complex. Our experiments performed in a native environment, both in organello and in vivo, show that Erv1 directly participates in Mia40–substrate complex dynamics by forming a ternary complex. Thus Mia40 in cooperation with Erv1 promotes the formation of two disulfide bonds in the substrate protein, ensuring the efficiency of oxidative folding in the intermembrane space of mitochondria.

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Herrmann, Johannes M., and Roman Köhl. "Catch me if you can! Oxidative protein trapping in the intermembrane space of mitochondria." Journal of Cell Biology 176, no. 5 (February 20, 2007): 559–63. http://dx.doi.org/10.1083/jcb.200611060.

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The intermembrane space (IMS) of mitochondria, the compartment that phylogenetically originated from the periplasm of bacteria, contains machinery to catalyze the oxidative folding of proteins (Mesecke, N., N. Terziyska, C. Kozany, F. Baumann, W. Neupert, K. Hell, and J.M. Herrmann. 2005. Cell. 121:1059–1069; Rissler, M., N. Wiedemann, S. Pfannschmidt, K. Gabriel, B. Guiard, N. Pfanner, and A. Chacinska. 2005. J. Mol. Biol. 353: 485–492; Tokatlidis, K. 2005. Cell. 121:965–96). This machinery introduces disulfide bonds into newly imported precursor proteins, thereby locking them in a folded conformation. Because folded proteins cannot traverse the translocase of the outer membrane, this stably traps the proteins in the mitochondria. The principle of protein oxidation in the IMS presumably has been conserved from the bacterial periplasm and has been adapted during evolution to drive the vectorial translocation of proteins from the cytosol into the mitochondria.

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Saris, Nina, Heidi Holkeri, Rachel A. Craven, Colin J. Stirling, and Marja Makarow. "The Hsp70 Homologue Lhs1p Is Involved in a Novel Function of the Yeast Endoplasmic Reticulum, Refolding and Stabilization of Heat-denatured Protein Aggregates." Journal of Cell Biology 137, no. 4 (May 19, 1997): 813–24. http://dx.doi.org/10.1083/jcb.137.4.813.

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Heat stress is an obvious hazard, and mechanisms to recover from thermal damage, largely unknown as of yet, have evolved in all organisms. We have recently shown that a marker protein in the ER of Saccharomyces cerevisiae, denatured by exposure of cells to 50°C after preconditioning at 37°C, was reactivated by an ATP-dependent machinery, when the cells were returned to physiological temperature 24°C. Here we show that refolding of the marker enzyme Hsp150Δ–β-lactamase, inactivated and aggregated by the 50°C treatment, required a novel ER-located homologue of the Hsp70 family, Lhs1p. In the absence of Lhs1p, Hsp150Δ–β-lactamase failed to be solubilized and reactivated and was slowly degraded. Coimmunoprecipitation experiments suggested that Lhs1p was somehow associated with heat-denatured Hsp150Δ– β-lactamase, whereas no association with native marker protein molecules could be detected. Similar findings were obtained for a natural glycoprotein of S. cerevisiae, pro-carboxypeptidase Y (pro-CPY). Lhs1p had no significant role in folding or secretion of newly synthesized Hsp150Δ–β-lactamase or pro-CPY, suggesting that the machinery repairing heat-damaged proteins may have specific features as compared to chaperones assisting de novo folding. After preconditioning and 50°C treatment, cells lacking Lhs1p remained capable of protein synthesis and secretion for several hours at 24°C, but only 10% were able to form colonies, as compared to wild-type cells. We suggest that Lhs1p is involved in a novel function operating in the yeast ER, refolding and stabilization against proteolysis of heatdenatured protein. Lhs1p may be part of a fundamental heat-resistant survival machinery needed for recovery of yeast cells from severe heat stress.

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Velasco, Dublang, Moro, and Muga. "The Complex Phosphorylation Patterns that Regulate the Activity of Hsp70 and Its Cochaperones." International Journal of Molecular Sciences 20, no. 17 (August 23, 2019): 4122. http://dx.doi.org/10.3390/ijms20174122.

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Proteins must fold into their native structure and maintain it during their lifespan to display the desired activity. To ensure proper folding and stability, and avoid generation of misfolded conformations that can be potentially cytotoxic, cells synthesize a wide variety of molecular chaperones that assist folding of other proteins and avoid their aggregation, which unfortunately is unavoidable under acute stress conditions. A protein machinery in metazoa, composed of representatives of the Hsp70, Hsp40, and Hsp110 chaperone families, can reactivate protein aggregates. We revised herein the phosphorylation sites found so far in members of these chaperone families and the functional consequences associated with some of them. We also discuss how phosphorylation might regulate the chaperone activity and the interaction of human Hsp70 with its accessory and client proteins. Finally, we present the information that would be necessary to decrypt the effect that post-translational modifications, and especially phosphorylation, could have on the biological activity of the Hsp70 system, known as the “chaperone code”.

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Kojer, Kerstin, Valentina Peleh, Gaetano Calabrese, Johannes M. Herrmann, and Jan Riemer. "Kinetic control by limiting glutaredoxin amounts enables thiol oxidation in the reducing mitochondrial intermembrane space." Molecular Biology of the Cell 26, no. 2 (January 15, 2015): 195–204. http://dx.doi.org/10.1091/mbc.e14-10-1422.

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The mitochondrial intermembrane space (IMS) harbors an oxidizing machinery that drives import and folding of small cysteine-containing proteins without targeting signals. The main component of this pathway is the oxidoreductase Mia40, which introduces disulfides into its substrates. We recently showed that the IMS glutathione pool is maintained as reducing as that of the cytosol. It thus remained unclear how equilibration of protein disulfides with the IMS glutathione pool is prevented in order to allow oxidation-driven protein import. Here we demonstrate the presence of glutaredoxins in the IMS and show that limiting amounts of these glutaredoxins provide a kinetic barrier to prevent the thermodynamically feasible reduction of Mia40 substrates by the IMS glutathione pool. Moreover, they allow Mia40 to exist in a predominantly oxidized state. Consequently, overexpression of glutaredoxin 2 in the IMS results in a more reduced Mia40 redox state and a delay in oxidative folding and mitochondrial import of different Mia40 substrates. Our findings thus indicate that carefully balanced glutaredoxin amounts in the IMS ensure efficient oxidative folding in the reducing environment of this compartment.

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Rabhi, Nabil, Elisabet Salas, Philippe Froguel, and Jean-Sébastien Annicotte. "Role of the Unfolded Protein Response inβCell Compensation and Failure during Diabetes." Journal of Diabetes Research 2014 (2014): 1–11. http://dx.doi.org/10.1155/2014/795171.

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Pancreaticβcell failure leads to diabetes development. During disease progression,βcells adapt their secretory capacity to compensate the elevated glycaemia and the peripheral insulin resistance. This compensatory mechanism involves a fine-tuned regulation to modulate the endoplasmic reticulum (ER) capacity and quality control to prevent unfolded proinsulin accumulation, a major protein synthetized within theβcell. These signalling pathways are collectively termed unfolded protein response (UPR). The UPR machinery is required to preserve ER homeostasis andβcell integrity. Moreover, UPR actors play a key role by regulating ER folding capacity, increasing the degradation of misfolded proteins, and limiting the mRNA translation rate. Recent genetic and biochemical studies on mouse models and human UPR sensor mutations demonstrate a clear requirement of the UPR machinery to preventβcell failure and increaseβcell mass and adaptation throughout the progression of diabetes. In this review we will highlight the specific role of UPR actors inβcell compensation and failure during diabetes.

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Raj, Kritika, Soram Idiyasan Chanu, and Surajit Sarkar. "Protein Misfolding and Aggregation in Neurodegenerative Disorders: Focus on Chaperone-Mediated Protein Folding Machinery." International Journal of Neurology Research 1, no. 2 (2015): 72–78. http://dx.doi.org/10.17554/j.issn.2313-5611.2015.01.14.

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Naganathan, Athi N. "Molecular origins of folding rate differences in the thioredoxin family." Biochemical Journal 477, no. 6 (March 18, 2020): 1083–87. http://dx.doi.org/10.1042/bcj20190864.

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Thioredoxins are a family of conserved oxidoreductases responsible for maintaining redox balance within cells. They have also served as excellent model systems for protein design and engineering studies particularly through ancestral sequence reconstruction methods. The recent work by Gamiz-Arco et al. [Biochem J (2019) 476, 3631–3647] answers fundamental questions on how specific sequence differences can contribute to differences in folding rates between modern and ancient thioredoxins but also among a selected subset of modern thioredoxins. They surprisingly find that rapid unassisted folding, a feature of ancient thioredoxins, is not conserved in the modern descendants suggestive of co-evolution of better folding machinery that likely enabled the accumulation of mutations that slow-down folding. The work thus provides an interesting take on the expected folding-stability-function constraint while arguing for additional factors that contribute to sequence evolution and hence impact folding efficiency.

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Anas, Mohammad, Ankita Shukla, Aradhya Tripathi, Varsha Kumari, Chetan Prakash, Priyabrata Nag, L. Sathish Kumar, Sandeep K. Sharma, Ravishankar Ramachandran, and Niti Kumar. "Structural–functional diversity of malaria parasite's PfHSP70-1 and PfHSP40 chaperone pair gives an edge over human orthologs in chaperone-assisted protein folding." Biochemical Journal 477, no. 18 (September 28, 2020): 3625–43. http://dx.doi.org/10.1042/bcj20200434.

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Plasmodium falciparum, the human malaria parasite harbors a metastable proteome which is vulnerable to proteotoxic stress conditions encountered during its lifecycle. How parasite's chaperone machinery is able to maintain its aggregation-prone proteome in functional state, is poorly understood. As HSP70–40 system forms the central hub in cellular proteostasis, we investigated the protein folding capacity of PfHSP70-1 and PfHSP40 chaperone pair and compared it with human orthologs (HSPA1A and DNAJA1). Despite the structural similarity, we observed that parasite chaperones and their human orthologs exhibit striking differences in conformational dynamics. Comprehensive biochemical investigations revealed that PfHSP70-1 and PfHSP40 chaperone pair has better protein folding, aggregation inhibition, oligomer remodeling and disaggregase activities than their human orthologs. Chaperone-swapping experiments suggest that PfHSP40 can also efficiently cooperate with human HSP70 to facilitate the folding of client-substrate. SPR-derived kinetic parameters reveal that PfHSP40 has higher binding affinity towards unfolded substrate than DNAJA1. Interestingly, the observed slow dissociation rate of PfHSP40-substrate interaction allows PfHSP40 to maintain the substrate in folding-competent state to minimize its misfolding. Structural investigation through small angle x-ray scattering gave insights into the conformational architecture of PfHSP70-1 (monomer), PfHSP40 (dimer) and their complex. Overall, our data suggest that the parasite has evolved functionally diverged and efficient chaperone machinery which allows the human malaria parasite to survive in hostile conditions. The distinct allosteric landscapes and interaction kinetics of plasmodial chaperones open avenues for the exploration of small-molecule based antimalarial interventions.

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Journal articles on the topic 'Protein folding machinery'

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