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Mechanistic Insights Into Cytosolic Molecular Chaperones in Protein Unfolding and Disaggregation Unicentre CH-1015 Lausanne http://serval.unil.ch Year : 2014 MECHANISTIC INSIGHTS INTO CYTOSOLIC MOLECULAR CHAPERONES IN PROTEIN UNFOLDING AND DISAGGREGATION Mattoo Rayees Mattoo Rayees, 2014, MECHANISTIC INSIGHTS INTO CYTOSOLIC MOLECULAR CHAPERONES IN PROTEIN UNFOLDING AND DISAGGREGATION Originally published at : Thesis, University of Lausanne Posted at the University of Lausanne Open Archive http://serval.unil.ch Document URN : urn:nbn:ch:serval-BIB_EA49B7E040F21 Droits d’auteur L'Université de Lausanne attire expressément l'attention des utilisateurs sur le fait que tous les documents publiés dans l'Archive SERVAL sont protégés par le droit d'auteur, conformément à la loi fédérale sur le droit d'auteur et les droits voisins (LDA). A ce titre, il est indispensable d'obtenir le consentement préalable de l'auteur et/ou de l’éditeur avant toute utilisation d'une oeuvre ou d'une partie d'une oeuvre ne relevant pas d'une utilisation à des fins personnelles au sens de la LDA (art. 19, al. 1 lettre a). A défaut, tout contrevenant s'expose aux sanctions prévues par cette loi. Nous déclinons toute responsabilité en la matière. Copyright The University of Lausanne expressly draws the attention of users to the fact that all documents published in the SERVAL Archive are protected by copyright in accordance with federal law on copyright and similar rights (LDA). Accordingly it is indispensable to obtain prior consent from the author and/or publisher before any use of a work or part of a work for purposes other than personal use within the meaning of LDA (art. 19, para. 1 letter a). Failure to do so will expose offenders to the sanctions laid down by this law. We accept no liability in this respect. Département de biologie moléculaire végétale MECHANISTIC INSIGHTS INTO CYTOSOLIC MOLECULAR CHAPERONES IN PROTEIN UNFOLDING AND DISAGGREGATION Thèse de doctorat ès sciences de la vie (Ph.D.) Présentée à la Faculté de biologie et de médecine de l’Université de Lausanne par RAYEES U. H. MATTOO Biochemistry diplômé ou Master de l’Université Aligarh Inde. Jury Prof. Jan Roelof van der Meer, Président Prof. Pierre Goloubinoff, Directeur de thèse Prof. Anat Ben-Zvi, expert Prof. Didier Picard, expert Lausanne, 2014. TABLE OF CONTENT Table of Content………………………………………………………………………..….. I Graphical Abstract…….………………….……………………………………...……..…. II Abstract………………………………………………………………….……………….... III Résumé…………………………………………………………………………………….. IV Acknowledgements.…..………………………………………………………………….... V General Overview…….…..……………………………………………………………….. VI-XII Chapter 1 Introduction: Recruiting unfolding chaperones to solubilize misfolded recombinant proteins (Mattoo and Goloubinoff, 2014b). Chapter 2: Biophysical characterization of two different stable misfolded monomeric polypeptides that are chaperone-amenable substrates (Natalello et al., 2013). Chapter 3: Hsp110 is a bona fide chaperone using ATP to unfold stable misfolded polypeptides and reciprocally collaborate with Hsp70 to solubilize protein aggregates (Mattoo et al., 2013). Chapter 4: GroEL and CCT are catalytic unfoldases mediating out-of-cage polypeptide refolding without ATP (Priya et al., 2013). Chapter 5: Stable α-synuclein oligomers strongly inhibit chaperone activity of the hsp70 system by weak interactions with j-domain co-chaperones (Hinault et al., 2010). Chapter 6: Meta-analysis of heat- and chemically upregulated chaperone genes in plant and human cells (Finka et al., 2011). Chapter 7, Conclusion: Molecular chaperones are nano-machines that catalytically unfold misfolded and alter-natively folded proteins (Mattoo and Goloubinoff, 2014a). Perspectives I Thesis Graphical Abstract MECHANISTIC INSIGHTS INTO CYTOSOLIC MOLECULAR CHAPERONES IN PROTEIN UNFOLDING AND DISAGGREGATION Cytosolic molecular chaperones reactivate misfolded or aggregated proteins by their polypeptide unfoldase activity. Protein synthesized de novo follow a native folding pathway under optimal conditions to acquire a terminal tertiary functional structure or may assemble to form a functional quaternary oligomer (upper pathway). Under stress or non-native conditions, protein may misfold (2) and enter an aggregation pathway (lower pathway), leading to the formation of aggregates and fibrils that can be cytotoxic. Chapter (2) presents an innovative method of preparation and biophysical characterization of stable misfolded monomers that were paradigmatic of the earliest species in the aggregation process and were unique chaperone amenable substrates that I used in most of the subsequent chapters of my thesis. In chapter (3), I addressed the disaggregation mechanism of stable protein aggregates by human Hsp70 and Hsp110 that acted as equal partners and synergistically combined their individual ATP-consuming polypeptide-unfoldase activity to reactivate stable protein aggregates. In chapter (4), my collaborators and I, showed that Hsp60 could act as a polypeptide unfoldase at reactivating stable misfolded proteins without ATP and without necessarily encaging them. In chapter (5) we investigated the role of Hsp40 (J-protein) at targeting Hsp70 onto the misfolded substrates and the inhibitory effect of potentially toxic protein aggregates on J- proteins that rendered Hsp70 unfolding activity less efficient, as in Parkinson’s diseases. In chapter (6) we performed an innovative type of meta-analysis of chaperone expressomic data under various stress conditions that revealed possible co-expressions between core chaperone machineries and their co-chaperone regulators. Encircled numbers in the figure represent chapters of the thesis. II Abstract Under optimal non-physiological Hsp110 collaborated with Hsp70 in the conditions of low concentrations and low disaggregation of stable protein aggregates in temperatures, proteins may spontaneously fold to which Hsp70 and Hsp110 acted as equal partners the native state, as all the information for folding that synergistically combined their individual lies in the amino acid sequence of the polypeptide. ATP-consuming polypeptide unfoldase activities However, under conditions of stress or high to reactivate the misfolded/aggregated proteins protein crowding as inside cells, a polypeptide may (Chapter 3). Using FT-rhodanese as substrate, we misfold and enter an aggregation pathway resulting found that chaperonins (GroEL and CCT) could in the formation of misfolded conformers and catalytically reactivate misfolded rhodanese fibrils, which can be toxic and lead to monomers in the absence of ATP. Also, our results neurodegenerative illnesses, such as Alzheimer’s, suggested that encaging of an unfolding Parkinson’s or Huntington’s diseases and aging in polypeptide inside the GroEL cavity under a general. To avert and revert protein misfolding and GroES cap was not an obligatory step as generally aggregation, cells have evolved a set of proteins thought (Chapter 4). Further, we investigated the called molecular chaperones. Here, I focussed on role of Hsp40, a J-protein co-chaperone of Hsp70, the human cytosolic chaperones Hsp70 (DnaK) in targeting misfolded polypeptides substrates onto and Hsp110, and co-chaperone Hsp40 (DnaJ), and Hsp70 for unfolding. We found that even a large the chaperonin CCT (GroEL). The cytosolic excess of monomeric unfolded α-synuclein did not molecular chaperones Hsp70s/Hsp110s and the inhibit DnaJ, whereas, in contrast, stable misfolded chaperonins are highly upregulated in bacterial and α-synuclein oligomers strongly inhibited the human cells under different stresses and are DnaK-mediated chaperone reaction by way of involved both in the prevention and the reversion sequestering the DnaJ co-chaperone. This work of protein misfolding and aggregation. Hsp70 revealed that DnaJ could specifically distinguish, works in collaboration with Hsp40 to reactivate and bind potentially toxic stably aggregated misfolded or aggregated proteins in a strict ATP species, such as soluble α-synuclein oligomers dependent manner. Chaperonins (CCT and GroEL) involved in Parkinson’s disease, and with the help also unfold and reactivate stably misfolded of DnaK and ATP convert them into from proteins but we found that it needed to use the harmless natively unfolded α-synuclein monomers energy of ATP hydrolysis in order to evict over- (chapter 5). Finally, our meta-analysis of sticky misfolded intermediates that inhibited the microarray data of plant and animal tissues treated unfoldase catalytic sites. with various chemicals and abiotic stresses, revealed possible co-expressions between core In this study, we initially characterized a chaperone machineries and their co-chaperone particular type of inactive misfolded monomeric regulators. It clearly showed that protein luciferase and rhodanese species that were misfolding in the cytosol elicits a different obtained by repeated cycles of freeze-thawing response, consisting of upregulating the synthesis (FT). These stable misfolded monomeric mainly of cytosolic chaperones, from protein conformers (FT-luciferase and FT-rhodanese) had misfolding in the endoplasmic reticulum (ER) that exposed hydrophobic residues and were enriched elicited a typical unfolded protein response (UPR), with wrong β-sheet structures (Chapter 2). Using consisting of upregulating the synthesis mainly of FT-luciferase as substrate, we found that the ER chaperones. We proposed that drugs that best Hsp70 orthologs, called Hsp110 (Sse in yeast), mimicked heat or UPR stress at increasing the acted similarly to Hsp70 as were bona fide ATP- chaperone load in the cytoplasm or ER fuelled polypeptide
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