title: Crystal structure of human Gadd45γ [corrected] reveals an active dimer.
abstract: 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 Gadd45γ [corrected], 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 Gadd45γ [corrected] 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 Gadd45γ [corrected] 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.
authors: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors: Wenzheng
authors: W
authors: Zhang
authors: Sheng
authors: S
authors: Fu
authors: Xuefeng
authors: X
authors: Liu
authors: Xuelian
authors: X
authors: Zhao
authors: Wenchi
authors: W
authors: Zhang
authors: Wei
authors: W
authors: Peng
authors: Congying
authors: C
authors: Wu
authors: Yuanyuan
authors: Y
authors: Li
authors: Xuemei
authors: X
authors: Li
authors: Mark
authors: M
authors: Bartlam
authors: Zong-Hao
authors: ZH
authors: Zeng
authors: Qimin
authors: Q
authors: Zhan
authors: Zihe
authors: Z
authors: Rao
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D016203:CDC2 Protein Kinase; D002453:Cell Cycle; D002470:Cell Survival; D018360:Crystallography, X-Ray; D019926:Cyclin B / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D018844:Cyclin-Dependent Kinases; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D014466:Ultraviolet Rays; D000097642:GADD45 Proteins
chemical_list: D016203:CDC2 Protein Kinase; D019926:Cyclin B; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases; D047908:Intracellular Signaling Peptides and Proteins; D018809:Proliferating Cell Nuclear Antigen; C485654:GADD45G protein, human; D000097642:GADD45 Proteins; C528899:CDK1 protein, human