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Prot Cell    2011, Vol. 2 Issue (10) : 814-826    https://doi.org/10.1007/s13238-011-1090-6      PMID: 22058036
RESEARCH ARTICLE
Crystal structure of human Gadd45 reveals an active dimer
Wenzheng Zhang1,2,3, Sheng Fu1, Xuefeng Liu4, Xuelian Zhao4, Wenchi Zhang1, Wei Peng1, Congying Wu3, Yuanyuan Li3, Xuemei Li1, Mark Bartlam1,2, Zong-Hao Zeng1(), Qimin Zhan4(), Zihe Rao1,2,3
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
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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 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.
Keywords crystal structure      Gadd45      dimer      DNA repair      growth inhibition      apoptosis     
Corresponding Author(s): Zeng Zong-Hao,Email:zzh@ibp.ac.cn (Z.-H. Zeng); Zhan Qimin,Email:zhanqimin@pumc.edu.cn (Q. Zhan)   
Issue Date: 01 October 2011
 Cite this article:   
Wenzheng Zhang,Sheng Fu,Xuefeng Liu, et al. Crystal structure of human Gadd45 reveals an active dimer[J]. Prot Cell, 2011, 2(10): 814-826.
 URL:  
https://academic.hep.com.cn/pac/EN/10.1007/s13238-011-1090-6
https://academic.hep.com.cn/pac/EN/Y2011/V2/I10/814
Fig.1  The structure of human Gadd45.
The sequence folds into five α helices and five β strands, including three loops, sequentially arranged as H1-B1-H2-B2-L1-H3-B3-H4-L2-B4-L3-H5-B5. The five β strands spacially arranged as a β sheet, B1-B4-B2-B3-B5, surounded by the helices. Figures 1-4 are created using Molscript () and Raster3D ().
Fig.1  The structure of human Gadd45.
The sequence folds into five α helices and five β strands, including three loops, sequentially arranged as H1-B1-H2-B2-L1-H3-B3-H4-L2-B4-L3-H5-B5. The five β strands spacially arranged as a β sheet, B1-B4-B2-B3-B5, surounded by the helices. Figures 1-4 are created using Molscript () and Raster3D ().
Fig.2  The human Gadd45γ dimer structures.
The 2-fold crystallographic axis relating the two monomers is nearly parallel to H3 and is just at the middle point of the two H3’s (the cross in A). Therefore, the dimer is formed by parallell packing of the four α helices, two H2’s and two H3’s. (A) The view along the 2-fold axis; (B) The side view of the packing of the two H3’s.
Fig.2  The human Gadd45γ dimer structures.
The 2-fold crystallographic axis relating the two monomers is nearly parallel to H3 and is just at the middle point of the two H3’s (the cross in A). Therefore, the dimer is formed by parallell packing of the four α helices, two H2’s and two H3’s. (A) The view along the 2-fold axis; (B) The side view of the packing of the two H3’s.
Fig.3  Close packing of the four helices in human Gadd45γ dimer.
Helices of the two monomers are colored, in green and blue, respectively. Numbers and red lines indicating the atomic distances in unit of ?. The interleaved packing of the four helices lets the H3 reach the sunken surface in between of H2 and H3 on the opposite monomer. One may notice that in a monomer, the residue Ile81 on H3 directs to H2 and B2 (not shown), not quite a surface residue.
Fig.3  Close packing of the four helices in human Gadd45γ dimer.
Helices of the two monomers are colored, in green and blue, respectively. Numbers and red lines indicating the atomic distances in unit of ?. The interleaved packing of the four helices lets the H3 reach the sunken surface in between of H2 and H3 on the opposite monomer. One may notice that in a monomer, the residue Ile81 on H3 directs to H2 and B2 (not shown), not quite a surface residue.
Fig.4  Packing of the antiparallell dimer identified by Schrag et al.
(A) The four helices are packed in a ridge-to-ridge manner. Hollow spaces that allow solvents exsit in between the four helices. (B) Packing of the two H3 helices. Only part of the helices takes part in interaction.
Fig.4  Packing of the antiparallell dimer identified by Schrag et al.
(A) The four helices are packed in a ridge-to-ridge manner. Hollow spaces that allow solvents exsit in between the four helices. (B) Packing of the two H3 helices. Only part of the helices takes part in interaction.
Fig.5  Binding of human Gadd45γ and its mutants to PCNA (A) or p21 and cdc2 (B).
HeLa cell lysates were incubated with human Gadd45γ and its mutants, and a pull-down assay was performed to detect interactions with PCNA, p21 or cdc2. Actin levels in 10 μL total material were used as input control. (C) The putative PCNA-binding region on the bottom of the full-length human Gadd45γ dimer. (D) The equivalent region of the truncated mouse Gadd45γ dimer, shown in a similar orientation as C. Fig. 5C and 5D are drawn with PyMol (www.pymol.org).
Fig.5  Binding of human Gadd45γ and its mutants to PCNA (A) or p21 and cdc2 (B).
HeLa cell lysates were incubated with human Gadd45γ and its mutants, and a pull-down assay was performed to detect interactions with PCNA, p21 or cdc2. Actin levels in 10 μL total material were used as input control. (C) The putative PCNA-binding region on the bottom of the full-length human Gadd45γ dimer. (D) The equivalent region of the truncated mouse Gadd45γ dimer, shown in a similar orientation as C. Fig. 5C and 5D are drawn with PyMol (www.pymol.org).
Fig.6  Colony formation efficiency of human Gadd45γ and its mutants in HeLa and EC9706 cells.
Transfected cells were selected with G418 for 2-3 weeks, and the surviving colonies were counted after staining with 0.5% crystal violet. The numbers of G418 resistant colonies in control vector transfected cells were set to 100%. Columns show the mean of three separate experiments; bars show the SD.
Fig.6  Colony formation efficiency of human Gadd45γ and its mutants in HeLa and EC9706 cells.
Transfected cells were selected with G418 for 2-3 weeks, and the surviving colonies were counted after staining with 0.5% crystal violet. The numbers of G418 resistant colonies in control vector transfected cells were set to 100%. Columns show the mean of three separate experiments; bars show the SD.
Fig.7  Cell cycle profile of human Gadd45γ and its mutants in HeLa cells.
Cells were transfected with the indicated pcDNA3.1(+) vectors. Cell cycle distribution of Gadd45γ, mutant forms, and the empty control vector were measured by propidium iodide (PI) staining followed by flow cytometry after transfection for 48 h. Results are the mean±SD from triplicate experiments.
Fig.7  Cell cycle profile of human Gadd45γ and its mutants in HeLa cells.
Cells were transfected with the indicated pcDNA3.1(+) vectors. Cell cycle distribution of Gadd45γ, mutant forms, and the empty control vector were measured by propidium iodide (PI) staining followed by flow cytometry after transfection for 48 h. Results are the mean±SD from triplicate experiments.
Fig.8  Effects of human Gadd45γ and its mutants on both low and high doses of UV-induced apoptosis in HeLa cells.
(A) Typical cytograms for empty control vector, Gadd45γ, and A47R+I76E+L80E+A83R mutant are presented. Nuclear DNA was stained with DAPI. The transfected cells were monitored by the expression of Myc or Myc-fusion protein as stained in red. The Myc-positive apoptotic cells were indicated by arrowheads. (B) Quantitive analysis of apoptosis. Apoptotic rates were determined by dividing the number of Myc-positive cells that exhibit apoptotic morphology by the total number of Myc-positive cells. At least 400 cells from six randomly chosen fields were counted for each data point. Data are represented as mean±SD.
Fig.8  Effects of human Gadd45γ and its mutants on both low and high doses of UV-induced apoptosis in HeLa cells.
(A) Typical cytograms for empty control vector, Gadd45γ, and A47R+I76E+L80E+A83R mutant are presented. Nuclear DNA was stained with DAPI. The transfected cells were monitored by the expression of Myc or Myc-fusion protein as stained in red. The Myc-positive apoptotic cells were indicated by arrowheads. (B) Quantitive analysis of apoptosis. Apoptotic rates were determined by dividing the number of Myc-positive cells that exhibit apoptotic morphology by the total number of Myc-positive cells. At least 400 cells from six randomly chosen fields were counted for each data point. Data are represented as mean±SD.
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