1sjt
From Proteopedia
(New page: 200px<br /> <applet load="1sjt" size="450" color="white" frame="true" align="right" spinBox="true" caption="1sjt" /> '''MINI-PROINSULIN, TWO CHAIN INSULIN ANALOG M...) |
|||
| Line 1: | Line 1: | ||
| - | [[Image:1sjt.gif|left|200px]]<br /> | + | [[Image:1sjt.gif|left|200px]]<br /><applet load="1sjt" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1sjt" size=" | + | |
caption="1sjt" /> | caption="1sjt" /> | ||
'''MINI-PROINSULIN, TWO CHAIN INSULIN ANALOG MUTANT: DES B30, HIS(B 10)ASP, PRO(B 28)ASP, NMR, 20 STRUCTURES'''<br /> | '''MINI-PROINSULIN, TWO CHAIN INSULIN ANALOG MUTANT: DES B30, HIS(B 10)ASP, PRO(B 28)ASP, NMR, 20 STRUCTURES'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Protein minimization highlights essential determinants of structure and | + | 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. |
==Disease== | ==Disease== | ||
| Line 11: | Line 10: | ||
==About this Structure== | ==About this Structure== | ||
| - | 1SJT is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http:// | + | 1SJT is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1SJT OCA]. |
==Reference== | ==Reference== | ||
| Line 17: | Line 16: | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Protein complex]] | [[Category: Protein complex]] | ||
| - | [[Category: Burke, G | + | [[Category: Burke, G T.]] |
| - | [[Category: Chu, Y | + | [[Category: Chu, Y C.]] |
| - | [[Category: Hu, S | + | [[Category: Hu, S Q.]] |
| - | [[Category: Hua, Q | + | [[Category: Hua, Q X.]] |
| - | [[Category: Jia, W | + | [[Category: Jia, W H.]] |
| - | [[Category: Katsoyannis, P | + | [[Category: Katsoyannis, P G.]] |
| - | [[Category: Wang, S | + | [[Category: Wang, S H.]] |
| - | [[Category: Weiss, M | + | [[Category: Weiss, M A.]] |
[[Category: diabetes]] | [[Category: diabetes]] | ||
[[Category: disease mutation]] | [[Category: disease mutation]] | ||
| Line 31: | Line 30: | ||
[[Category: signal]] | [[Category: signal]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:02:12 2008'' |
Revision as of 13:02, 21 February 2008
|
MINI-PROINSULIN, TWO CHAIN INSULIN ANALOG MUTANT: DES B30, HIS(B 10)ASP, PRO(B 28)ASP, NMR, 20 STRUCTURES
Contents |
Overview
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.
Disease
Known diseases associated with this structure: Diabetes mellitus, rare form OMIM:[176730], Hyperproinsulinemia, familial OMIM:[176730], MODY, one form OMIM:[176730]
About this Structure
1SJT is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
Reference
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 Thu Feb 21 15:02:12 2008
Categories: Homo sapiens | Protein complex | Burke, G T. | Chu, Y C. | Hu, S Q. | Hua, Q X. | Jia, W H. | Katsoyannis, P G. | Wang, S H. | Weiss, M A. | Diabetes | Disease mutation | Glucose metabolism | Hormone | Signal
