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Type: Journal article
Title: Solution structure and backbone dynamics of long -[Arg³] insulin-like growth factor-I
Other Titles: Solution structure and backbone dynamics of long -[Arg(3)] insulin-like growth factor-I
Author: Laajoki, L.
Francis, G.
Wallace, J.
Carver, J.
Keniry, M.
Citation: Journal of Biological Chemistry, 2000; 275(14):10009-10015
Publisher: Amer Soc Biochemistry Molecular Biology Inc
Issue Date: 2000
ISSN: 0021-9258
Statement of
Leanne G. Laajoki, Geoffrey L. Francis, John C. Wallace, John A. Carver, and Max A. Keniry
Abstract: Long-[Arg3]insulin-like growth factor-I (IGF-I) is a potent analog of insulin-like growth factor-I that has been modified by a Glu3 Arg mutation and a 13-amino acid extension appended to the N terminus. We have determined the solution structure of 15N-labeled Long-[Arg3]-IGF-I using high resolution NMR and restrained molecular dynamics techniques to a precision of 0.82 ± 0.28 Å root mean square deviation for the backbone heavy atoms in the three -helices and 3.5 ± 0.9 Å root mean square deviation for all backbone heavy atoms excluding the 8 N-terminal residues and the 8 C-terminal eight residues. Overall, the structure of the IGF-I domain is consistent with earlier studies of IGF-I with some minor changes remote from the N terminus. The major variations in the structure, compared with IGF-I, occur at the N terminus with a substantial reorientation of the N-terminal three residues of the IGF-I domain. These results are interpreted in terms of the lower binding affinity for insulin-like growth factor-binding proteins. The backbone dynamics of Long-[Arg3]IGF-I were investigated using 15N nuclear spin relaxation and the heteronuclear nuclear Overhauser enhancement (NOE). There is a considerable degree of flexibility in Long-[Arg3]IGF-I, even in the -helices, as indicated by an average {1H}15N NOE of 0.55 for the regions. The largest heteronuclear NOEs are observed in the helical regions, lower heteronuclear NOEs are observed in the C-domain loop separating helix 1 from helix 2, and negative heteronuclear NOEs are observed in the N-terminal extension and at the C terminus. Despite these data indicating conformational flexibity for the N-terminal extension, slow amide proton exchange was observed for some residues in this region, suggesting some transitory structure does exist, possibly a molten helix. A certain degree of flexibility may be necessary in all insulin-like growth factors to enable association with various receptors and binding proteins.
Description: Copyright © 2008 by the American Society for Biochemistry and Molecular Biology, Inc.
DOI: 10.1074/jbc.275.14.10009
Appears in Collections:Aurora harvest 2
Molecular and Biomedical Science publications

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