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Genetic and Biochemical Analyses of Hsp70-Hsp40 Interactions in Saccharomyces Cerevisiae Provides Insights Into Specificity and Mechanisms of Regulation

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Genetic and Biochemical Analyses of Hsp70-Hsp40 Interactions in Saccharomyces Cerevisiae Provides Insights Into Specificity and Mechanisms of Regulation GENETIC AND BIOCHEMICAL ANALYSES OF HSP70-HSP40 INTERACTIONS IN SACCHAROMYCES CEREVISIAE PROVIDES INSIGHTS INTO SPECIFICITY AND MECHANISMS OF REGULATION by Shruthi Sridhar Vembar M.Sc. (Hons.) Biological Sciences, Birla Institute of Technology and Science, Pilani, India Submitted to the Graduate Faculty of Arts and Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2009 UNIVERSITY OF PITTSBURGH FACULTY OF ARTS AND SCIENCES This dissertation was presented by Shruthi Sridhar Vembar It was defended on May 7, 2009 and approved by Karen M. Arndt, Professor, Biological Sciences Paula Grabowski, Professor, Biological Sciences Anthony M. Schwacha, Assistant Professor, Biological Sciences John L. Woolford, Professor, Biological Sciences, Carnegie Mellon University Dissertation Advisor: Jeffrey L. Brodsky, Professor, Biological Sciences ii Copyright © by Shruthi Sridhar Vembar 2009 iii GENETIC AND BIOCHEMICAL ANALYSES OF HSP70-HSP40 INTERACTIONS IN SACCHAROMYCES CEREVISIAE PROVIDE INSIGHTS INTO SPECIFICITY AND MECHANISMS OF REGULATION Shruthi Sridhar Vembar, Ph.D. University of Pittsburgh, 2009 Heat s hock pr oteins o f 70kDa ( Hsp70s) a nd their J dom ain-containing H sp40 c ofactors a re conserved chaperone pairs that facilitate diverse cellular processes. One essential Hsp70 in the endoplasmic r eticulum ( ER) lum en, BiP (Kar2p i n yeast), participates i n polypeptide translocation into the ER, protein folding, and ER-associated de gradation (ERAD). Like ot her Hsp70s, BiP cont ains an N -terminal ATPase do main, followed b y a s ubstrate bi nding dom ain and a C-terminal lid domain. To better define how substrate affinity and Hsp40 interaction affect BiP f unction, I constructed and characterized a mutation, R 217A, i n t he put ative J dom ain- interacting surface of yeast BiP. The mutation compromises ATPase stimulation by Sec63p, an Hsp40 required for t ranslocation, but stimulation by J em1p, an Hsp40 required for E RAD, is robust. In accordance with these data, yeast expressing R217A BiP exhibit translocation defects, but no E RAD defects, and a genetic interaction study using this mutant yielded data consistent with defects in translocation. In contrast, mutations in the substrate binding domain that either disrupt an ionic contact with the lid or remove this domain are deficient for peptide-stimulated ATPase activity. Expression of these mutants in yeast results in varying translocation and ERAD defects. Taken together, t hese d ata i ndicate t hat B iP can distinguish between its E R-resident cochaperones, and that optimal substrate binding is a key determinant of BiP function. Next, I te sted the h ypothesis tha t the f unctional s pecificity of Hsp70s i s r egulated by cognate Hsp40s. If this is true, one might expect divergent Hsp70-Hsp40 pairs to be unable to iv function in vivo. H owever, I discovered that a mammalian ER-lumenal Hsp40, E Rdj3, w hen directed to the yeast cytosol, was able to rescue the temperature-sensitive growth phenotype of yeast c ontaining mutant a lleles in two cytosolic H sp40s, HLJ1 and YDJ1. M oreover, E Rdj3 activated the ATPase activity of Ssa1p, the yeast cytosolic Hsp70 that partners with Hlj1p and Ydj1p. Intriguingly, ERdj3 mutants that were compromised for substrate binding were unable to rescue t he hlj1ydj1 growth defect, even t hough t hey stimulated Ssa1p ATPase act ivity. These data suggest that the substrate binding properties of certain Hsp40s—not simply the formation of unique Hsp70-Hsp40 pairs—is critical to specify in vivo function. v TABLE OF CONTENTS PREFACE ................................................................................................................................... XV 1.0 INTRODUCTION ........................................................................................................ 1 1.1 HEAT SHOCK PROTEINS ............................................................................... 3 1.2 BIP IS AN ER LUMENAL HSP70 .................................................................... 5 1.2.1 Insights from Hsp70 structural studies ......................................................... 6 1.2.2 Yeast BiP’s Hsp40 cochaperones .................................................................. 17 1.2.2.1 The human Hsp40, ERdj3 .................................................................. 20 1.2.3 Nucleotide Exchange Factors for yeast BiP and other BiP-interacting proteins ........................................................................................................................ 21 1.2.4 BiP is required for co- and post-translational protein translocation across the ER membrane ...................................................................................................... 23 1.2.5 BiP participates in nascent protein folding in the ER ................................ 27 1.2.6 BiP-mediated recognition and targeting of misfolded proteins for ER- associated degradation ............................................................................................... 31 1.2.7 BiP is required for the induction of the unfolded protein response .......... 38 1.2.8 Other BiP functions ....................................................................................... 42 1.2.9 BiP and human disease.................................................................................. 44 1.3 A PREVIEW OF CHAPTERS 2 AND 3 ......................................................... 47 vi 2.0 THE TRANSLOCATION-SPECIFIC BIP MUTANT, R217A, GENETICALLY INTERACTS WITH ILM1, A NOVEL PLAYER IN CO-TRANSLOCATIONAL PROTEIN TRANSLOCATION ACROSS THE ER MEMBRANE...................................... 49 2.1 MATERIALS AND METHODS ...................................................................... 52 2.1.1 Yeast strains and plasmids............................................................................ 52 2.1.2 Protein purification ....................................................................................... 56 2.1.3 ATP hydrolysis and limited proteolysis assays ........................................... 57 2.1.4 Serial dilutions ............................................................................................... 58 2.1.5 Preparation of yeast cell extracts and immunoblotting ............................. 59 2.1.6 Pulse-labeling of cells and immunoprecipitation ........................................ 59 2.1.7 β-galactosidase assays to measure the induction of the UPR .................... 61 2.1.8 In vitro translocation and ERAD assays ...................................................... 62 2.1.9 Purification of the Sec63 complex ................................................................ 63 2.1.10 UPR-based genetic analysis ......................................................................... 64 2.1.11 Native immunoprecipitations of FLAG-tagged Ilm1p .............................. 65 2.1.12 Cycloheximide-chase ERAD assays ............................................................ 65 2.1.13 Data analysis ................................................................................................. 66 2.2 RESULTS ........................................................................................................... 66 2.2.1 Generation of the yeast BiP mutants, R217A, K584X and S493F ............ 66 2.2.2 R217A BiP exhibits defective interaction with Sec63p and Scj1p............. 70 2.2.3 High level expression of BiP mutants results in yeast strains displaying varied sensitivity to elevated temperature and ER stress ...................................... 73 vii 2.2.4 Lower level expression of the K584X and S493F BiP mutants results in yeast strains exhibiting sensitivity to elevated temperature and ER stress .......... 78 2.2.5 The TEF1-R217A strain exhibits a defect in protein translocation across the ER membrane, but is proficient for ERAD and ER protein folding .............. 84 2.2.6 Sec63 complex formation is reduced for R217A BiP.................................. 91 2.2.7 Scj1p and Jem1p function redundantly in TEF1-R217A yeast ................. 93 2.2.8 Identification of genetic interactions specific for the R217A BiP allele .... 97 2.2.9 Ilm1p is a novel player during protein translocation across the ER membrane ................................................................................................................. 100 2.2.10 Deletion of ilm1 does not result in ERAD defects .................................... 105 2.3 DISCUSSION ................................................................................................... 106 2.3.1 Identification of a translocation-specific BiP mutant, R217A ................. 109 2.3.2 Substrate binding mutants of BiP affect ER homeostasis and multiple BiP functions .................................................................................................................... 111 2.3.3 Characterization of the genetic interactions of R217A BiP ..................... 112 2.3.4 Ilm1p, a previously uncharacterized protein, plays a role in the translocation of BiP .................................................................................................. 114 2.3.5 Perspective .................................................................................................... 115 3.0 COMPLEMENTATION OF HSP40-DEPENDENT YEAST PHENOTYPES DIFFER IN THEIR REQUIREMENTS FOR THE J DOMAIN AND SUBSTRATE BINDING ACTIVITIES OF A MAMMALIAN HOMOLOG ............................................
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