β细胞转录因子中与糖尿病相关的突变会破坏二聚化界面中一条反平行“迷你拉链”的稳定性。
Diabetes-associated mutations in a beta-cell transcription factor destabilize an antiparallel "mini-zipper" in a dimerization interface.
作者信息
Hua Q X, Zhao M, Narayana N, Nakagawa S H, Jia W, Weiss M A
机构信息
Department of Biochemistry, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106-4935, USA.
出版信息
Proc Natl Acad Sci U S A. 2000 Feb 29;97(5):1999-2004. doi: 10.1073/pnas.97.5.1999.
Abstract
Maturity-onset diabetes of the young, a monogenic form of Type II diabetes mellitus, is most commonly caused by mutations in hepatic nuclear factor 1alpha (HNF-1alpha). Here, the dimerization motif of HNF-1alpha is shown to form an intermolecular four-helix bundle. One face contains an antiparallel coiled coil whereas the other contains splayed alpha-helices. The "mini-zipper" is complementary in structure and symmetry to the top surface of a transcriptional coactivator (dimerization cofactor of homeodomains). The bundle is destabilized by a subset of mutations associated with maturity-onset diabetes of the young. Impaired dimerization of a beta-cell transcription factor thus provides a molecular mechanism of metabolic deregulation in diabetes mellitus.
摘要
青年发病的成年型糖尿病是2型糖尿病的一种单基因形式，最常见的病因是肝细胞核因子1α（HNF-1α）发生突变。在此，研究表明HNF-1α的二聚化基序形成了一个分子间四螺旋束。其一面包含一个反平行卷曲螺旋，而另一面则包含呈展开状的α螺旋。这个“迷你拉链”在结构和对称性上与转录共激活因子（同源结构域二聚化辅因子）的顶面互补。该螺旋束会因与青年发病的成年型糖尿病相关的一部分突变而变得不稳定。因此，β细胞转录因子二聚化受损为糖尿病中的代谢失调提供了一种分子机制。
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