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

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• 作者：Andrzej M. Brzozowski ; Eleanor J. Dodson ; Guy G. Dodson ; Garib N. Murshudov ; Chandra Verma ; Johan P. Turkenburg ; Frederik M. de Bree ; and Zbigniew Dauter
• 刊名：Biochemistry
• 出版年：2002
• 出版时间：July 30, 2002
• 年：2002
• 卷：41
• 期：30
• 页码：9389 - 9397
• 全文大小：808K
• 年卷期：v.41,no.30(July 30, 2002)
• ISSN：1520-4995

文摘

Human insulin-like growth factors I and II (hIGF-I, hIGF-II) are potent stimulators of celland growth processes. They display high sequence similarity to both the A and B chains of insulin butcontain an additional connecting C-domain, which reflects their secretion without specific packaging orprecursor conversion. IGFs also have an extension at the C-terminus known as the D-domain. This paperdescribes four homologous hIGF-1 structures, obtained from crystals grown in the presence of the detergentSB12, which reveal additional detail in the C- and D-domains. Two different detergent binding modesobserved in the crystals may reflect different hIGF-I biological properties such as the interaction withIGF binding proteins and self-aggregation. While the helical core of hIGF-I is very similar to that ininsulin, 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 extensiveloop protruding 20 Å from the core, which results in a substantially different conformation for the receptorbinding epitope in hIGF-I compared to insulin. One notable feature of the structures presented here isdemonstration of peptide-bond cleavage between Ser35 and Arg36 resulting in an apparent gap betweenresidues 35 and 39. The equivalent region of proinsulin is involved in hormone processing demanding areassessment of the structural integrity of hIGF-I in relation to its biological function.