Walid A. Houry Department of Biochemistry University of Toronto
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1 Walid A. Houry Department of Biochemistry University of Toronto JBB2026 October, 2016 Protein Folding and Misfolding in the Cell Inclusion Bodies & Aggresomes 3 Molecular Chaperones 2 1 Crowding and Viscosity
2 in a test tube folding N in a living cell N C Denatured Synthesized on a ribosome unassisted assisted C Folding Process C N N
3 The Cytoplasm is Very Crowded and Viscous Red proteins Green ribosomes Blue RNA/DNA adapted from D. S. Goodsell, Trends in Biochemical Sciences 16: , 1991.
4 Consequences of crowding Excluded volume favors compact conformations: Native state is favored Favors association reactions Crowding reduces the diffusional mobility of macromolecules The rates of diffusion controlled reactions are lowered However, the rates of much slower reactions limited by the formation of transition-state maybe enhanced, depending on the volume exclusion properties of the transition state. Minton Current Opinion in Structural Biology ((2000), vol 10, pp Based on the study of van den Berg et al. (EMBO J, 2000, vol 19, pp ) on the oxidative refolding of hen lysozyme, the data suggests that crowding does not alter substantially the energetics of the protein folding reaction. However, the presence of high concentrations of macromolecules results in the acceleration of the fast track of the refolding process whereas the slow track is substantially retarded. The results can be explained by preferential excluded volume stabilization of compact states relative to more unfolded states.
5 energetics
6 Example of energy
7 Not well
8 concept Concept of a Molecular Chaperone A protein which transiently binds to and stabilizes an unstable conformer of another protein, and through regulated binding and release, facilitates its correct fate in vivo: be it folding following de novo synthesis, transit across a membrane, or stress-induced denaturation, oligomeric assembly, interaction with other cellular components, switching between active and inactive conformations, intracellular transport, or proteolytic degradation, either singly or with the help of cofactors
9 Chaperones in E. coli 1. Hsp100: ClpA, ClpB, ClpX, HslU 2. Hsp90: HtpG 3. Hsp70/Hsp40: DnaK, Hsc66, Hsc62, YEGD/ DnaJ, Hsc20, CbpA, DJLA 4. Hsp60/Hsp10: GroEL/GroES 5. Small Heat Shock: HslJ, HslO, HslR, HtrC, IbpA, IbpB, SspA, SspB Other chaperone families include: - Peptidyl-prolyl cis-trans isomerases, - Disulfide bond formation proteins, - Phage shock proteins, - General stress response proteins, - Pilus chaperone family, - Acid shock proteins, - Osmotic shock proteins, - Membrane damage proteins, - Hypotheticals 6. Cold Shock Proteins: CspA, CspB, CspC, CspD, CspE, CspF, CspG, CspH, CspI
10 Chaperones to be discussed Trigger Factor DnaK/DnaJ/GrpE GroEL/GroES Outline Structure Function in vitro Function in vivo
11 Chaperones in E. coli biosynthesis
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13 TF PPIase domain is similar to FKBP, but TF does not bind to FK506 from Mycoplasma genitalium Putative active site Vogtherr et al., JMB (2002), vol 318, pp
14 Prokaryotic ribosome Entrance-exit channel: Contains trna binding sites, mrna-retaining site of the small subunit, and the peptidyl transferase center, PTC, of the large subunit. An a-trna enter this intersubunit space sequentially from one side and deacylated trnas leave the ribosome from the other side. Also, the mrna chain is drawn through the hole from its 5' to 3' ends. Polypeptide exit tunnel E P A
15 E13 in L23 is important for TF binding Kramer et al. Nature (2002), vol 419, pp
16 Structure of E. coli TF The authors solved the structure of fulllength E. coli TF. They also solved the structure of N- terminal fragment of TF bound to 50S ribosomal subunit from Haloacula marismortui. TF forms a shape resembling a crouching dragon with overall dimensions of 122 x 59 x 63 angstroms 3. The N-terminal domain of TF is solely responsible for binding to ribosome. The PPIase domain is away from the ribosome. Ferbitz et al. Nature, vol 431, p 590 (2004)
17 TF might form a cradle over the polypeptide exit tunnel TF might promote cotranslational folding The folding space formed between TF and the ribosome is sufficiently large to accommodate a domain of the size of the 14 kda lysozyme. Ferbitz et al. Nature, vol 431, p 590 (2004)
18 The cradle model is controversial Schlunzen et al. solved the structure of TF-BD ribosome complex from Deinococcus radiodurans. They found that a b hairpin loop of L24 occupies the space proposed to be present for protein folding according to the cradle model. Schlunzen et al. Structure, vol 13, p 1685 (2005) 18
19 TF undergoes a conformational change upon binding the ribosome TF bound to ribosome Free TF The hydrophobic crevice in the TF binding Domain seems to open up upon ribosome binding 19
20 NMR: Substrate (PhoA)-binding sites in TF
21 NMR: Substrate (PhoA)-binding sites in TF (A) The TF residues identified by NMR to interact with unfolded protein substrates are colored blue on the crystal structure of free E. coli TF [Protein Data Bank (PDB) ID 1W26]. The four main binding sites are labeled A, B, C, and D (in red). The dashed lines indicate the domain boundaries. The two structural protrusions in the SBD are labeled arm 1 and arm 2. An additional binding site, located in arm 1, is used by TF to interact with some of the substrates (see Fig. 7A and fig. S11). (B) Expanded view of the four substrate-binding sites in TF identified by the NMR titration experiments. The hydrophobic residues that make up the substrate-binding sites are shown as sticks. (C) The hydrophobic residues in TF are colored green, whereas all other residues are colored white. (D) TF sequence conservation is color-mapped on the TF structure. The residues that make up the substrate-binding sites are the bestconserved along with the ribosome-binding loop (RB loop). Saoi et al. Science. Vol 344, p (2014)
22 Structural basis for the formation of the TF-PhoA complex The three TF molecules in complex with PhoA (Fig. 4A) are linked by long (~80 to 90 amino acids), flexible regions of PhoA that are not bound by TF. Thus, the three PhoAbound TF molecules tumble and behave as independent entities. The high-resolution structure of each of the three complexes (TF PhoA a-c, TF PhoA d-e, and TF PhoA f-g ) were determined.
23 The dynamic cycling model for TF function Kaiser et al., Nature, vol. 444, p455 (2006) 23
24 Based on peptide array studies, TF preferentially binds to a stretch of eight amino acids enriched in basic and aromatic residues and with a net positive charge. Patzelt et al. (2001) PNAS, vol 98, pp
25
26 Structure of DnaK
27 Structure of DnaJ and GrpE
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32 The binding motif of DnaJ consists of a hydrophobic core of approximately eight residues enriched for aromatic, large aliphatic hydrophobic residues, and arginine. Rudiger et al. EMBO J (2001), vol 20, pp
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38 Endogenous substrates of DnaK from proteomics studies
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42 EL fig GroEL: view from top GroEL: view from top residues colored red are implicated in polypeptide binding
43 GroEL cycle ~ 15 s
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45 GroEL function in vivo 1. Around 10% of newly-translated protein require GroEL for de novo folding. 2. GroEL is also required for the conformational maintenance of preexisting proteins. 3. Identification of GroEL substrates. 4. Characterization of identified substrates.
46 Flux of substrates through GroEL on 2D gels
47 Kinetic complexity of the passage of substrates through GroEL
48 model
49 The GroEL substrates
50 Structural classification of GroEL substrates hydrophilic hydrophobic
51 Substrate recognition by GroEL
52 Substrate Selectivity of GroEL Typical GroEL Substrate 1. Molecular weight > 20 KDa 2. Multiple b domains 3. Surface of buried b sheet is hydrophobic 4. No preference for proteins that have oligomeric states or discontinuous domains GroEL binding to its substrate 1. Mainly through hydrophobic interactions between the apical domains of GroEL and the surface of the b sheet 2. Other modes of binding to helices are also possible
53 Isolation of GroEL/GroES complexes with encapsulated substrates from Methanosarcina mazei Kerner et al. Cell 122, p 209 (2005)
54 Kerner et al. Cell 122, p 209 (2005) More controls: PK protection
55 Kerner et al. Cell 122, p 209 (2005) Identified ~250 as GroEL binding proteins (mostly enriched in TIM barrels)
56 Endogenous substrates of GroEL from proteomics studies
57 Flux of substrates through the different chaperones
58 Protein aggregation: inclusion bodies and aggresomes Protein aggregates can either be structured (amyloids) or amorphous. In either case, they tend too be insoluble and metabolically stable under physiological conditions. The accumulation of protein aggregates is tightly linked to neuronal degeneration (amyloid diseases, Alzheimer's disease, Parkinson's disease, Huntington's disease, alcoholic liver disease, etc.). Chaperones and proteases are part of the quality control machinery that suppresses the formation of protein aggregates. Schubert et al. (Nature, 2000, vol 404, pp ) suggest that an astonishingly high proportion (30%) of newly synthesized cellular proteins are defective ribosomal proteins that are apparently degraded by proteasomes shortly after synthesis.
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60 Inclusion body formation Mainly in bacteria Mainly in eukaryotes Kopito Trends in Cell Biology (2000), vol 10, pp
61 Definition of aggresome To emphasize the role of microtubules in the formation of inclusion bodies within the cytoplasm of mammalian cells and to highlight the distinction between microtubule-dependent inclusion bodies and those present in cells or organelles that lack a cytoskeleton, Johnston et al. (JCB, 1998, vol 143, pp ) proposed to call microtubule-dependent cytoplasmic inclusion bodies 'aggresomes'.
62 Aggresomes are microtubule-based inclusion bodies Kopito Trends in Cell Biology (2000), vol 10, pp
63 Composition of aggresomes Bacterial inclusion bodies are typically highly enriched for a single protein species. Aggresomes contain, in addition to the aggregated protein species, molecular chaperones (Hsc70, Hdj1, Hdj2, TriC), proteasomal subunits (19S and 26S) and intermediate filament proteins (vimentin and glial fibrillary acidic protein).
64 Rochet & Lansbury Current Opinion in Structural Biology ((2000), vol 10, pp 60-68
65 Chaperones in Protein Folding and Degradation From Wickner et al. Science 1999
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