Crystal structure of human Gadd45 reveals an active dimer  

作　　者：Wenzheng Zhang Sheng Fu Xuefeng Liu Xuelian Zhao Wenchi Zhang Wei Peng Congying Wu Yuanyuan Li Xuemei Li Mark Bartlam Zong-Hao Zeng Qimin Zhan Zihe Rao 

机构地区：[1]National Laboratory of Biomacromolecules,Institute of Biophysics,Chinese Academy of Sciences,Beijing 100101,China [2]Tianjin Key Laboratory of Protein Science,College of Life Sciences,Nankai University,Tianjin 300071,China [3]Laboratory of Structural Biology,Tsinghua University,Beijing 100084,China [4]State Key Laboratory of Molecular Oncology,Cancer Institute,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100021,China

出　　处：《Protein & Cell》2011年第10期814-826,共13页蛋白质与细胞（英文版）

基　　金：by the National Basic Research Program(973 Program)(Nos.2006CB806503,2007CB914301 and 2007CB914304);the National Programs for High Technology Research and Development Program(863 Program)(No.2006AA02A322);the National Major Project(Grant No.2009ZX10004-304).

摘　　要：The human Gadd45 protein family plays critical roles in DNA repair,negative growth control,genomic stability,cell cycle checkpoints and apoptosis.Here we report the crystal structure of human Gadd45,revealing a unique dimer formed via a bundle of four parallel helices,involving the most conserved residues among the Gadd45 isoforms.Mutational analysis of human Gadd45 identified a conserved,highly acidic patch in the central region of the dimer for interaction with the proliferating cell nuclear antigen(PCNA),p21 and cdc2,suggesting that the parallel dimer is the active form for the interaction.Cellular assays indicate that:(1)dimerization of Gadd45 is necessary for apoptosis as well as growth inhibition,and that cell growth inhibition is caused by both cell cycle arrest and apoptosis;(2)a conserved and highly acidic patch on the dimer surface,including the important residues Glu87 and Asp89,is a putative interface for binding proteins related to the cell cycle,DNA repair and apoptosis.These results reveal the mechanism of self-association by Gadd45 proteins and the importance of this self-association for their biological function.

关 键 词：crystal structure GADD45 DIMER DNA repair growth inhibition APOPTOSIS 

分 类 号：R73[医药卫生—肿瘤]