Brzozowski, A.M., Dodson, E.J., Dodson, G.G. et al. (5 more authors) (2002) Structural origins of the functional divergence of human insulin-like growth factor-I and insulin. Biochemistry, 41 (30). pp. 9389-9397. ISSN 1520-4995
Human insulin-like growth factors I and II (hIGF-I, hIGF-II) are potent stimulators of cell and growth processes. They display high sequence similarity to both the A and B chains of insulin but contain an additional connecting C-domain, which reflects their secretion without specific packaging or precursor conversion. IGFs also have an extension at the C-terminus known as the D-domain. This paper describes four homologous hIGF-1 structures, obtained from crystals grown in the presence of the detergent SB12, which reveal additional detail in the C- and D-domains. Two different detergent binding modes observed in the crystals may reflect different hIGF-I biological properties such as the interaction with IGF binding proteins and self-aggregation. While the helical core of hIGF-I is very similar to that in insulin, there are distinct differences in the region of hIGF-I corresponding to the insulin B chain C-terminus, residues B25−B30. In hIGF-I, these residues (24−29) and the following C-domain form an extensive loop protruding 20 Å from the core, which results in a substantially different conformation for the receptor binding epitope in hIGF-I compared to insulin. One notable feature of the structures presented here is demonstration of peptide-bond cleavage between Ser35 and Arg36 resulting in an apparent gap between residues 35 and 39. The equivalent region of proinsulin is involved in hormone processing demanding a reassessment of the structural integrity of hIGF-I in relation to its biological function.
|Institution:||The University of York|
|Academic Units:||The University of York > Chemistry (York)|
|Depositing User:||York RAE Import|
|Date Deposited:||13 Aug 2009 09:34|
|Last Modified:||13 Aug 2009 09:34|
|Publisher:||American Chemical Society|