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标题：Evolution of insulin at the edge of foldability and its medical implications
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作者：Nischay K. Rege ; Ming Liu ; Yanwu Yang 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2020
卷号：117
期号：47
页码：29618-29628
DOI：10.1073/pnas.2010908117
出版社：The National Academy of Sciences of the United States of America
摘要：Proteins have evolved to be foldable, and yet determinants of foldability may be inapparent once the native state is reached. Insight has emerged from studies of diseases of protein misfolding, exemplified by monogenic diabetes mellitus due to mutations in proinsulin leading to endoplasmic reticulum stress and β-cell death. Cellular foldability of human proinsulin requires an invariant Phe within a conserved crevice at the receptor-binding surface (position B24). Any substitution, even related aromatic residue Tyr B24 , impairs insulin biosynthesis and secretion. As a seeming paradox, a monomeric Tyr B24 insulin analog exhibits a native-like structure in solution with only a modest decrement in stability. Packing of Tyr B24 is similar to that of Phe B24 , adjoining core cystine B19–A20 to seal the core; the analog also exhibits native self-assembly. Although affinity for the insulin receptor is decreased ∼20-fold, biological activities in cells and rats were within the range of natural variation. Together, our findings suggest that the invariance of Phe B24 among vertebrate insulins and insulin-like growth factors reflects an essential role in enabling efficient protein folding, trafficking, and secretion, a function that is inapparent in native structures. In particular, we envision that the para -hydroxyl group of Tyr B24 hinders pairing of cystine B19–A20 in an obligatory on-pathway folding intermediate. The absence of genetic variation at B24 and other conserved sites near this disulfide bridge—excluded due to β-cell dysfunction—suggests that insulin has evolved to the edge of foldability. Nonrobustness of a protein’s fitness landscape underlies both a rare monogenic syndrome and “diabesity” as a pandemic disease of civilization.
关键词：evolutionary medicine ; unfolded protein response ; protein structure ; protein folding ; folding efficiency