1sjt: Difference between revisions
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'''MINI-PROINSULIN, TWO CHAIN INSULIN ANALOG MUTANT: DES B30, HIS(B 10)ASP, PRO(B 28)ASP, NMR, 20 STRUCTURES''' | '''MINI-PROINSULIN, TWO CHAIN INSULIN ANALOG MUTANT: DES B30, HIS(B 10)ASP, PRO(B 28)ASP, NMR, 20 STRUCTURES''' | ||
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[[Category: Wang, S H.]] | [[Category: Wang, S H.]] | ||
[[Category: Weiss, M A.]] | [[Category: Weiss, M A.]] | ||
[[Category: | [[Category: Diabetes]] | ||
[[Category: | [[Category: Disease mutation]] | ||
[[Category: | [[Category: Glucose metabolism]] | ||
[[Category: | [[Category: Hormone]] | ||
[[Category: | [[Category: Signal]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 08:47:37 2008'' | |||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | |||
Revision as of 08:47, 3 May 2008
MINI-PROINSULIN, TWO CHAIN INSULIN ANALOG MUTANT: DES B30, HIS(B 10)ASP, PRO(B 28)ASP, NMR, 20 STRUCTURES
OverviewOverview
Protein minimization highlights essential determinants of structure and function. Minimal models of proinsulin and insulin-like growth factor I contain homologous A and B domains as single-chain analogues. Such models (designated mini-proinsulin and mini-IGF-I) have attracted wide interest due to their native foldability but complete absence of biological activity. The crystal structure of mini-proinsulin, determined as a T3R3 hexamer, is similar to that of the native insulin hexamer. Here, we describe the solution structure of a monomeric mini-proinsulin under physiologic conditions and compare this structure to that of the corresponding two-chain analogue. The two proteins each contain substitutions in the B-chain (HisB10-->Asp and ProB28-->Asp) designed to destabilize self-association by electrostatic repulsion; the proteins differ by the presence or absence of a peptide bond between LysB29 and GlyA1. The structures are essentially identical, resembling in each case the T-state crystallographic protomer. Differences are observed near the site of cross-linking: the adjoining A1-A8 alpha-helix (variable among crystal structures) is less well-ordered in mini-proinsulin than in the two-chain variant. The single-chain analogue is not completely inactive: its affinity for the insulin receptor is 1500-fold lower than that of the two-chain analogue. Moreover, at saturating concentrations mini-proinsulin retains the ability to stimulate lipogenesis in adipocytes (native biological potency). These results suggest that a change in the conformation of insulin, as tethered by the B29-A1 peptide bond, optimizes affinity but is not integral to the mechanism of transmembrane signaling. Surprisingly, the tertiary structure of mini-proinsulin differs from that of mini-IGF-I (main-chain rms deviation 4.5 A) despite strict conservation of non-polar residues in their respective hydrophobic cores (side-chain rms deviation 4.9 A). Three-dimensional profile scores suggest that the two structures each provide acceptable templates for threading of insulin-like sequences. Mini-proinsulin and mini-IGF-I thus provide examples of homologous protein sequences encoding non-homologous structures.
About this StructureAbout this Structure
1SJT is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
Mini-proinsulin and mini-IGF-I: homologous protein sequences encoding non-homologous structures., Hua QX, Hu SQ, Jia W, Chu YC, Burke GT, Wang SH, Wang RY, Katsoyannis PG, Weiss MA, J Mol Biol. 1998 Mar 20;277(1):103-18. PMID:9514738 Page seeded by OCA on Sat May 3 08:47:37 2008