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1lkq
From Proteopedia
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|ACTIVITY= | |ACTIVITY= | ||
|GENE= | |GENE= | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY= | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1lkq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1lkq OCA], [http://www.ebi.ac.uk/pdbsum/1lkq PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1lkq RCSB]</span> | ||
}} | }} | ||
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==Overview== | ==Overview== | ||
The A and B chains of insulin combine to form native disulfide bridges without detectable isomers. The fidelity of chain combination thus recapitulates the folding of proinsulin, a precursor protein in which the two chains are tethered by a disordered connecting peptide. We have recently shown that chain combination is blocked by seemingly conservative substitutions in the C-terminal alpha-helix of the A chain. Such analogs, once formed, nevertheless retain high biological activity. By contrast, we demonstrate here that chain combination is robust to non-conservative substitutions in the N-terminal alpha-helix. Introduction of multiple glycine substitutions into the N-terminal segment of the A chain (residues A1-A5) yields analogs that are less stable than native insulin and essentially without biological activity. (1)H NMR studies of a representative analog lacking invariant side chains Ile(A2) and Val(A3) (A chain sequence GGGEQCCTSICSLYQLENYCN; substitutions are italicized and cysteines are underlined) demonstrate local unfolding of the A1-A5 segment in an otherwise native-like structure. That this and related partial folds retain efficient disulfide pairing suggests that the native N-terminal alpha-helix does not participate in the transition state of the reaction. Implications for the hierarchical folding mechanisms of proinsulin and insulin-like growth factors are discussed. | The A and B chains of insulin combine to form native disulfide bridges without detectable isomers. The fidelity of chain combination thus recapitulates the folding of proinsulin, a precursor protein in which the two chains are tethered by a disordered connecting peptide. We have recently shown that chain combination is blocked by seemingly conservative substitutions in the C-terminal alpha-helix of the A chain. Such analogs, once formed, nevertheless retain high biological activity. By contrast, we demonstrate here that chain combination is robust to non-conservative substitutions in the N-terminal alpha-helix. Introduction of multiple glycine substitutions into the N-terminal segment of the A chain (residues A1-A5) yields analogs that are less stable than native insulin and essentially without biological activity. (1)H NMR studies of a representative analog lacking invariant side chains Ile(A2) and Val(A3) (A chain sequence GGGEQCCTSICSLYQLENYCN; substitutions are italicized and cysteines are underlined) demonstrate local unfolding of the A1-A5 segment in an otherwise native-like structure. That this and related partial folds retain efficient disulfide pairing suggests that the native N-terminal alpha-helix does not participate in the transition state of the reaction. Implications for the hierarchical folding mechanisms of proinsulin and insulin-like growth factors are discussed. | ||
| - | |||
| - | ==Disease== | ||
| - | Known diseases associated with this structure: Diabetes mellitus, rare form OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176730 176730]], Hyperproinsulinemia, familial OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176730 176730]], MODY, one form OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176730 176730]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: mutant]] | [[Category: mutant]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 22:04:05 2008'' |
Revision as of 19:04, 30 March 2008
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| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
NMR STRUCTURE OF HUMAN INSULIN MUTANT ILE-A2-GLY, VAL-A3-GLY, HIS-B10-ASP, PRO-B28-LYS, LYS-B29-PRO, 20 STRUCTURES
Overview
The A and B chains of insulin combine to form native disulfide bridges without detectable isomers. The fidelity of chain combination thus recapitulates the folding of proinsulin, a precursor protein in which the two chains are tethered by a disordered connecting peptide. We have recently shown that chain combination is blocked by seemingly conservative substitutions in the C-terminal alpha-helix of the A chain. Such analogs, once formed, nevertheless retain high biological activity. By contrast, we demonstrate here that chain combination is robust to non-conservative substitutions in the N-terminal alpha-helix. Introduction of multiple glycine substitutions into the N-terminal segment of the A chain (residues A1-A5) yields analogs that are less stable than native insulin and essentially without biological activity. (1)H NMR studies of a representative analog lacking invariant side chains Ile(A2) and Val(A3) (A chain sequence GGGEQCCTSICSLYQLENYCN; substitutions are italicized and cysteines are underlined) demonstrate local unfolding of the A1-A5 segment in an otherwise native-like structure. That this and related partial folds retain efficient disulfide pairing suggests that the native N-terminal alpha-helix does not participate in the transition state of the reaction. Implications for the hierarchical folding mechanisms of proinsulin and insulin-like growth factors are discussed.
About this Structure
1LKQ is a Protein complex structure of sequences from [1]. Full crystallographic information is available from OCA.
Reference
Mechanism of insulin chain combination. Asymmetric roles of A-chain alpha-helices in disulfide pairing., Hua QX, Chu YC, Jia W, Phillips NF, Wang RY, Katsoyannis PG, Weiss MA, J Biol Chem. 2002 Nov 8;277(45):43443-53. Epub 2002 Aug 23. PMID:12196530
Page seeded by OCA on Sun Mar 30 22:04:05 2008
Categories: Protein complex | Chu, Y C. | Hua, Q X. | Jia, W. | Katsoyannis, P G. | Philips, N F. | Wang, R Y. | Weiss, M A. | Hormone | Human insulin | Mutant
