lec14-Chaperones and other Folding Helpers

lec14-Chaperones and other Folding Helpers - 7.88 Lecture...

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7.88 Lecture Notes - 14 7.24/7.88J/5.48J The Protein Folding Problem Chaperonins Chaperonins and Protein Misfolding Segue into GroEL Misfolding >> Kinetically trapped aggregates A. Chaperonins Just three experiments: 1) original RUBISCO set a, b, c 2) two stage Rubisco 3) Perhaps 1 generalized mitochondrial import experiment Chaperonins: Protein families that help proteins fold within cells: Maintain unfolded states for protein export or import Assist chain folding correctly within (stressed) cells Inhibit formation of misfolded, aggregated states Refold as proofreading function Select/unfold them for degradation The chaperonins were originally identified through convergence of three tracks: Plants: Rubisco synthesis in chloroplasts; Newly synthesized large subunit associated with Large Subunit Binding Protein: Phages: Host genes required for phage morphogenesis. Eukaryotes: Heat Shock genes turned on in fruit flies in response to heat Ubiquitous: present in all living cells that have been examined; highly homologous. Many other Stress Genes - O2, - toxins such as alcohol, - radiation Classes of Stress Proteins HSP 60s E. coli Yeast Mammals HSP 70s HSP 90s HSP104
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Chaperone proteins and their known functions in the cell Subcellular Location Organism Component Subunit Mr (kDa) The hsp 70 family Cytosol E. coli DnaK 69 Yeast Ssa1-4p 69-72 Mammals hsc70 Mitochondria Yeast Ssc1p 70 Endoplasmic reticulum Yeast Kar2p 78 Bip, Grp78 70 The hsp60 family Cytosol E.coli GroEL 58 GroES 10 Mitochondrial matrix Fungi, hsp60, 58-64 mammals hsp58 hsp10 10 Chloroplasts Plants Rubisco subunit binding protein 61 ( α -chain) 60 ( β -chain) SecB E. coli 17 The hsp90 family Cytosol Mammals hsp90 90 HSP60 class of chaperonins: GroEL/S Cpn60/cpn10 HSP 60 Purified by Roger Hendrix J. Mol. Biol (1989) 129 359 - 373. GroEL/ES 22 S 14 mer of subunits 60k GroE L arge + 7mer of 14k Gro E S mall. Tetradecamers Double barrel, cyclic seven-fold symmetry, and two fold reflection symmetry: 7 fold cyclic cap sits on one end in physiological mode
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Remind you that we have already shown that Folding Intermediates > Aggregate Aggregation is generally kinetic trap for the chains Folding intermediates likely to be intrinsically thermolabile with respect to native 1) Experiment 1: Long history of difficulty in understanding biosynthesis and in refolding protein in vitro from Chloroplasts. Best defined experimental work is function of E. coli GroE, on hetrologous substrate, RUBISCO - Ribulose bisphosphate decarboxylase. In higher plants this
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lec14-Chaperones and other Folding Helpers - 7.88 Lecture...

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