Mapping the functional surface of insulin by design: structure and function of a novel A-chain analogue

Journal of Molecular Biology
Q X HuaM A Weiss

Abstract

Functional surfaces of a protein are often mapped by combination of X-ray crystallography and mutagenesis. Such studies of insulin have yielded paradoxical results, suggesting that the native state is inactive and reorganizes on receptor binding. Of particular interest is the N-terminal alpha-helix of the A-chain. Does this segment function as an alpha-helix or reorganize as recently proposed in a prohormone-convertase complex? To correlate structure and function, we describe a mapping strategy based on protein design. The solution structure of an engineered monomer ([AspB10, LysB28, ProB29]-human insulin) is determined at neutral pH as a template for synthesis of a novel A-chain analogue. Designed by analogy to a protein-folding intermediate, the analogue lacks the A6-A11 disulphide bridge; the cysteine residues are replaced by serine. Its solution structure is remarkable for segmental unfolding of the N-terminal A-chain alpha-helix (A1 to A8) in an otherwise native subdomain. The structure demonstrates that the overall orientation of the A and B chains is consistent with reorganization of the A-chain's N-terminal segment. Nevertheless, the analogue's low biological activity suggests that this segment, a site of clinical mutat...Continue Reading

Citations

Sep 24, 1999·The Biochemical Journal·Y YuanJ G Tang
Jan 29, 2010·The Journal of Biological Chemistry·Yanwu YangMichael A Weiss
Oct 24, 2009·The Journal of Biological Chemistry·Ming LiuMichael A Weiss
Jan 29, 2010·The Journal of Biological Chemistry·Yanwu YangMichael A Weiss
Mar 12, 2008·The Journal of Biological Chemistry·Qing-xin HuaMichael A Weiss
Apr 28, 2009·The Journal of Biological Chemistry·Michael A Weiss
Nov 17, 2007·Antioxidants & Redox Signaling·Zhan-Yun GuoYou-Min Feng
Dec 14, 2001·Protein Science : a Publication of the Protein Society·Bin XuMichael A Weiss
Aug 25, 2007·Nanomedicine·Manuela KochMarkus Meuwly
Mar 1, 2013·The Journal of Biological Chemistry·Lenka ŽákováAndrzej M Brzozowski
Jul 28, 2004·Journal of Molecular Biology·Kun HuangMichael A Weiss
Nov 14, 1998·Journal of Molecular Biology·H B OlsenN C Kaarsholm
Mar 26, 2010·Physical Chemistry Chemical Physics : PCCP·Ziad GanimAndrei Tokmakoff
Oct 24, 2003·Protein Science : a Publication of the Protein Society·Xiao-Yuan JiaYou-Min Feng
Nov 23, 2016·The Journal of Biological Chemistry·Krystel El HageMichael A Weiss
Aug 28, 2002·The Journal of Biological Chemistry·Qing-Xin HuaMichael A Weiss
Sep 20, 2018·Diabetes, Obesity & Metabolism·Ming LiuPeter Arvan
Sep 20, 2018·Diabetes, Obesity & Metabolism·Michael A Weiss, Michael C Lawrence
Jan 1, 1997·Biopolymers·C McInnes, B D Sykes
Apr 6, 2007·Biopolymers·John P MayerRichard D DiMarchi
Jun 10, 2006·The Journal of Biological Chemistry·Qing-Xin HuaMichael A Weiss
Jul 26, 2006·The Journal of Biological Chemistry·Qing-xin HuaMichael A Weiss
Jan 1, 1997·Critical Reviews in Biotechnology·J Inbar, I Chet
May 30, 2012·Annals of the New York Academy of Sciences·Daniel F BerensonMichael A Weiss
Jul 6, 2014·The Journal of Biological Chemistry·Vijay PandyarajanMichael A Weiss
Jun 14, 2013·Proteins·Yang LiKun Huang

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