lecture_11legge

lecture_11legge - Protein Folding Protein folding problem...

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1 Protein Folding Purification and Myoglobin Lecture 11 (29 September 2009) Protein folding problem • Levinthal paradox – 100aa protein three conformations => 3 100 possible orientations => random search for native Protein Folding structure would take longer than the age of the universe • Prediction of three dimensional structure from its amino acid sequence • Translate “Linear” DNA Sequence data to spatial information Sidechain locations in proteins • Non-polar sidechains (Val, Leu, Ile, Met, and Phe) occur mostly in the interior of a protein keeping them out of the water (hydro-phobic effect) • Charged polar residue (Arg His Lys Asp and Charged polar residues (Arg, His, Lys, Asp, and Glu) are normally located on the surface of the protein in contact with water. • Uncharged polar residues (Ser, Thr, Asn, Gln, and Tyr) are usually on the protein surface but also occur in the interior of the protein. Protein Stability Forces that stabilize protein structure: 1, 2, 3 1. The Hydrophobic Effect 2. Electrostatic Interactions 3Ch i lC li k Ion pair (salt bridge) of myoglobin Zinc finger: Nucleic acid-binding proteins 3. Chemical Cross-links Protein Folding Pathways Proteins can be unfolded/denatured. Denatured proteins can be refolded, sometimes requiring helper proteins, and this refolding takes place via preferred pathways. Common thought is that secondary structures form first, eventually collapsing due to the formation of hydrophobic cores. Folding funnel Energy-entropy relationship for protein folding
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2 Molecular chaperons Molecular chaperones: (1) Hsp70 proteins function as monomer (2) Chaperonins, large multisubunit proteins (3) Hsp90 proteins for the folding of proteins involved with signal transduction GroEL GroES Reaction cycle of the GroEL/ES cycle 1. GroEL ring binding 7 ATP and a substrate (improperly folded protein). Then it binds a GroES cap to become the cis ring. 2. The cis ring catalyzes the hydrolysis of its 7 ATP. 3. A 2nd substrate binds to the trans ring followed by 7 ATP. 4. The binding of substrate and ATP to the trabs ring conformationally induces the cis ring to release its bound GroES, 7 ADP, and the better folded substrate.The trans ring becomes the cis ring. Protein disulfide Isomerase Diseases Caused by Protein Misfolding Alzheimer’s disease Transmissible spongiform encephalopathies (TSE) Amyloidoses Prion protein conformation Once it has formed, an amyloid fibril is virtually indestructible (interchain H- bonds). It seems likely that protein folding pathways have evolved not only to allow polypeptides to assume stable native structures but also to avoid A model of an amyloid fibril forming interchain H-bonds that would lead to fibril formation . The factors that trigger amyloid formation remain obscure, even when mutation (hereditary amyloidoses) or infection (TSEs) appear to be the cause.
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lecture_11legge - Protein Folding Protein folding problem...

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