与DNA结合的Smad MH1结构域的晶体结构：对转化生长因子-β信号通路中DNA结合的见解

Crystal structure of a Smad MH1 domain bound to DNA: insights on DNA binding in TGF-beta signaling.

作者信息

Shi Y, Wang Y F, Jayaraman L, Yang H, Massagué J, Pavletich N P

机构信息

Department of Molecular Biology, Princeton University, Lewis Thomas Laboratory, New Jersey 08544, USA.

出版信息

Cell. 1998 Sep 4;94(5):585-94. doi: 10.1016/s0092-8674(00)81600-1.

DOI:10.1016/s0092-8674(00)81600-1

PMID:9741623

Abstract

The Smad family of proteins, which are frequently targeted by tumorigenic mutations in cancer, mediate TGF-beta signaling from cell membrane to nucleus. The crystal structure of a Smad3 MH1 domain bound to an optimal DNA sequence determined at 2.8 A resolution reveals a novel DNA-binding motif. In the crystals, base-specific DNA recognition is provided exclusively by a conserved 11-residue beta hairpin that is embedded in the major groove of DNA. A surface loop region, to which tumorigenic mutations map, has been identified as a functional surface important for Smad activity. This structure establishes a framework for understanding how Smad proteins may act in concert with other transcription factors in the regulation of TGF-beta-responsive genes.

摘要

Smad蛋白家族在癌症中常成为致瘤突变的靶点，介导转化生长因子-β（TGF-β）从细胞膜到细胞核的信号传导。以2.8埃分辨率测定的与最佳DNA序列结合的Smad3 MH1结构域的晶体结构揭示了一种新的DNA结合基序。在晶体中，碱基特异性DNA识别完全由一个保守的11个残基的β发夹提供，该发夹嵌入DNA的大沟中。已确定一个致瘤突变所在的表面环区域是对Smad活性很重要的功能表面。这一结构为理解Smad蛋白如何与其他转录因子协同作用来调控TGF-β反应基因建立了一个框架。