1sjt
MINI-PROINSULIN, TWO CHAIN INSULIN ANALOG MUTANT: DES B30, HIS(B 10)ASP, PRO(B 28)ASP, NMR, 20 STRUCTURES
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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.
DiseaseDisease
Known diseases associated with this structure: Diabetes mellitus, rare form OMIM:[176730], Hyperproinsulinemia, familial OMIM:[176730], MODY, one form OMIM:[176730]
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
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