3gky

The Structural Basis of an ER Stress-Associated Bottleneck in a Protein Folding Landscape

spinqualitylabelsall models 3gky, resolution 1.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3gky is a 4 chain structure with sequence from Sus scrofa. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.8Å Ligands: CL, IPH, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function INS_PIG Insulin decreases blood glucose concentration. It increases cell permeability to monosaccharides, amino acids and fatty acids. It accelerates glycolysis, the pentose phosphate cycle, and glycogen synthesis in liver. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed Protein evolution is constrained by folding efficiency ("foldability") and the implicit threat of toxic misfolding. A model is provided by proinsulin, whose misfolding is associated with beta-cell dysfunction and diabetes mellitus. An insulin analogue containing a subtle core substitution (Leu(A16) --> Val) is biologically active, and its crystal structure recapitulates that of the wild-type protein. As a seeming paradox, however, Val(A16) blocks both insulin chain combination and the in vitro refolding of proinsulin. Disulfide pairing in mammalian cell culture is likewise inefficient, leading to misfolding, endoplasmic reticular stress, and proteosome-mediated degradation. Val(A16) destabilizes the native state and so presumably perturbs a partial fold that directs initial disulfide pairing. Substitutions elsewhere in the core similarly destabilize the native state but, unlike Val(A16), preserve folding efficiency. We propose that Leu(A16) stabilizes nonlocal interactions between nascent alpha-helices in the A- and B-domains to facilitate initial pairing of Cys(A20) and Cys(B19), thus surmounting their wide separation in sequence. Although Val(A16) is likely to destabilize this proto-core, its structural effects are mitigated once folding is achieved. Classical studies of insulin chain combination in vitro have illuminated the impact of off-pathway reactions on the efficiency of native disulfide pairing. The capability of a polypeptide sequence to fold within the endoplasmic reticulum may likewise be influenced by kinetic or thermodynamic partitioning among on- and off-pathway disulfide intermediates. The properties of [Val(A16)]insulin and [Val(A16)]proinsulin demonstrate that essential contributions of conserved residues to folding may be inapparent once the native state is achieved. Crystal structure of a "nonfoldable" insulin: impaired folding efficiency despite native activity.,Liu M, Wan ZL, Chu YC, Aladdin H, Klaproth B, Choquette M, Hua QX, Mackin RB, Rao JS, De Meyts P, Katsoyannis PG, Arvan P, Weiss MA J Biol Chem. 2009 Dec 11;284(50):35259-72. Epub 2009 Oct 22. PMID:19850922 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Insulin 3D Structures

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