Structural Origins of the Functional Divergence of Human Insulin-Like Growth Factor-I and Insulin

• Published in: Biochemistry (Easton) Vol. 41; no. 30; pp. 9389 - 9397
• Main Authors: Brzozowski, Andrzej M, Dodson, Eleanor J, Dodson, Guy G, Murshudov, Garib N, Verma, Chandra, Turkenburg, Johan P, de Bree, Frederik M, Dauter, Zbigniew
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 30-07-2002
• Subjects: Amino Acid Sequence; Humans; Hydrogen Bonding; Insulin - chemistry; Insulin-Like Growth Factor I - chemistry; Models, Molecular; Molecular Sequence Data; Protein Conformation; Sequence Homology, Amino Acid
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/bi020084j

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.