Sunderman F W, Barber A M
Department of Laboratory Medicine, University of Connecticut Medical School, Farmington 06032.
Ann Clin Lab Sci. 1988 Jul-Aug;18(4):267-88.
Certain DNA-binding proteins that regulate gene expression contain single or multiple copies of short polypeptide sequences, approximately 30 residues long, consisting of combinations of four Cys or His residues at defined spacing, so that Zn++ is complexed in tetrahedral coordination with the respective thiol-sulfur and/or imidazole-nitrogen atoms. The Zn++ ion evidently serves as a strut that stabilizes folding of the domain into a 'finger-loop', which is capable of site-specific binding to double-stranded DNA. This article reviews the evidence (a) that finger-loop domains have been highly conserved during evolution, (b) that they furnish one of the fundamental mechanisms for regulating gene expression, and (c) that a metal ion (e.g., Zn++) is required for binding of finger-loops to DNA and for their biological functions. The authors' search of amino acid sequences of 38 transforming proteins identified possible finger-loop domains in the myc, fms, fps, raf-1, rfp, src, syn, yes, erbA, int-1, and TGF-alpha gene-products. The search incidentally revealed possible finger-loop domains in human insulin receptor, which may provide a mechanistic explanation for recent observations that insulin, after binding to its cell surface receptor, is translocated to hepatocyte nuclei and becomes bound to chromatin. Zn++-coordination sites in finger-loop domains are proposed as potential targets for metal toxicity; substitution of Ni++, Co++, or Cd++ for Zn++ in finger-loops of transforming proteins is suggested as an hypothetical mechanism for metal carcinogenesis.
某些调节基因表达的DNA结合蛋白含有单拷贝或多拷贝的短多肽序列，长度约为30个残基，由四个半胱氨酸（Cys）或组氨酸（His）残基按特定间距组合而成，使得Zn++以四面体配位方式与相应的硫醇硫原子和/或咪唑氮原子络合。Zn++离子显然起到支柱的作用，稳定结构域折叠成“指环状”，这种结构能够与双链DNA进行位点特异性结合。本文综述了以下证据：（a）指环状结构域在进化过程中高度保守；（b）它们提供了调节基因表达的一种基本机制；（c）指环状结构域与DNA结合及其生物学功能需要金属离子（如Zn++）。作者对38种转化蛋白的氨基酸序列进行搜索，在myc、fms、fps、raf-1、rfp、src、syn、yes、erbA、int-1和TGF-α基因产物中鉴定出可能的指环状结构域。该搜索偶然发现人类胰岛素受体中可能存在指环状结构域，这可能为最近的观察结果提供一个机制解释，即胰岛素与细胞表面受体结合后，会转移到肝细胞核并与染色质结合。指环状结构域中的Zn++配位位点被认为是金属毒性的潜在靶点；在转化蛋白的指环状结构中用Ni++、Co++或Cd++取代Zn++被认为是金属致癌作用的一种假说机制。
