Toward the Insulin−IGF-I Intermediate Structures: Functional and Structural Properties of the [TyrB25NMePheB26] Insulin Mutant
The origins of differentiation of insulin from insulin-like growth factor I (IGF-I) are still unknown. To address the problem of a structural and biological switch from the mostly metabolic hormonal activity of insulin to the predominant growth factor activities of IGF-I, an insulin analogue with IG...
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Published in | Biochemistry (Easton) Vol. 43; no. 51; pp. 16293 - 16300 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Chemical Society
28.12.2004
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Subjects | |
Online Access | Get full text |
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Summary: | The origins of differentiation of insulin from insulin-like growth factor I (IGF-I) are still unknown. To address the problem of a structural and biological switch from the mostly metabolic hormonal activity of insulin to the predominant growth factor activities of IGF-I, an insulin analogue with IGF-I-like structural features has been synthesized. Insulin residues PheB25 and TyrB26 have been swapped with the IGF-I-like Tyr24 and Phe25 sequence with a simultaneous methylation of the peptide nitrogen of residue PheB26. These modifications were expected to introduce a substantial kink in the main chain, as observed at residue Phe25 in the IGF-I crystal structure. These alterations should provide insight into the structural origins of insulin−IGF-I structural and functional divergence. The [TyrB25NMePheB26] mutant has been characterized, and its crystal structure has been determined. Surprisingly, all of these changes are well accommodated within an insulin R6 hexamer. Only one molecule of each dimer in the hexamer responds to the structural alterations, the other remaining very similar to wild-type insulin. All alterations, modest in their scale, cumulate in the C-terminal part of the B-chain (residues B23−B30), which moves toward the core of the insulin molecule and is associated with a significant shift of the A1 helix toward the C-terminus of the B-chain. These changes do not produce the expected bend of the main chain, but the fold of the mutant does reflect some structural characteristics of IGF-1, and in addition establishes the COA19−NHB25 hydrogen bond, which is normally characteristic of T-state insulin. |
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Bibliography: | istex:ACAA0585A21BC3E97C31E5032ACCDC37A673983A ark:/67375/TPS-X7N7MJ07-B The work of L.Ž. and J.B. was supported by Research Project Z4 055 905, N° K5011112 awarded by the Academy of Sciences of the Czech Republic and the Center for Molecular and Gene Biotechnoloy supported by the Czech Ministry of Education (code LN00B030). ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0006-2960 1520-4995 |
DOI: | 10.1021/bi048856u |