title: Molecular architecture of the ErbB2 extracellular domain homodimer.
abstract: Human epidermal growth factor receptors (HERs or ErbBs) play crucial roles in numerous cellular processes. ErbB2 is a key member of ErbB family, and its overexpression is recognized as a frequent molecular abnormality. In cancer, this overexpression correlates with aggressive disease and poor patient outcomes. Dimer-dependent phosphorylation is a key event for the signal transduction of ErbBs. However, the molecular mechanism of the dimerization of ErbB2 remains elusive. In the present work, we report the homodimer architecture of the ErbB2 extracellular domain (ECD) which is unique compared with other dimer-models of ErbBs. The structure of the ErbB2 ECD homodimer represents a "back to head" interaction, in which a protruding β-hairpin arm in domain II of one ErbB2 protomer is inserted into a C-shaped pocket created by domains I-III of the adjacent ErbB2 protomer. This dimerized architecture and its impact on the phosphorylation of ErbB2 intracellular domain were further verified by a mutagenesis study. We also elucidated the different impacts of two clinically administered therapeutic antibodies, trastuzumab and pertuzumab, on ErbB2 dimerization. This information not only provides an understanding of the molecular mechanism of ErbBs dimerization but also elucidates ErbB2-targeted therapy at the molecular level.
authors: International Joint Cancer Institute & Translational Medicine Research Institute, the Second Military Medical University, Shanghai, 200433, P.R. China.|National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing, 100101, P.R. China.|Laboratory of Structural Biology and MOE Laboratory of Protein Science, School of Medicine, Tsinghua University, Beijing, 100084, P.R. China.|Cancer Center, Chinese PLA General Hospital & Chinese PLA Medical School, Beijing, 100853, P.R. China.
authors: Shi
authors: S
authors: Hu
authors: National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing, 100101, P.R. China.|Laboratory of Structural Biology and MOE Laboratory of Protein Science, School of Medicine, Tsinghua University, Beijing, 100084, P.R. China.
authors: Yuna
authors: Y
authors: Sun
authors: School of Medicine, Nankai University, Tianjin, 300071, P.R. China.|National Engineering Research Center for Antibody Medicine and Shanghai Key Laboratory of Cell Engineering & Antibody, Shanghai, 201203, P.R. China.|School of Pharmacy, Liaocheng University, Liaocheng, Shandong, 252000, P.R. China.
authors: Yanchun
authors: Y
authors: Meng
authors: School of Medicine, Nankai University, Tianjin, 300071, P.R. China.
authors: Xiaoze
authors: X
authors: Wang
authors: Cancer Center, Chinese PLA General Hospital & Chinese PLA Medical School, Beijing, 100853, P.R. China.|School of Medicine, Nankai University, Tianjin, 300071, P.R. China.
authors: Weili
authors: W
authors: Yang
authors: Cancer Center, Chinese PLA General Hospital & Chinese PLA Medical School, Beijing, 100853, P.R. China.
authors: Wenyan
authors: W
authors: Fu
authors: International Joint Cancer Institute & Translational Medicine Research Institute, the Second Military Medical University, Shanghai, 200433, P.R. China.|National Engineering Research Center for Antibody Medicine and Shanghai Key Laboratory of Cell Engineering & Antibody, Shanghai, 201203, P.R. China.
authors: Huaizu
authors: H
authors: Guo
authors: International Joint Cancer Institute & Translational Medicine Research Institute, the Second Military Medical University, Shanghai, 200433, P.R. China.|National Engineering Research Center for Antibody Medicine and Shanghai Key Laboratory of Cell Engineering & Antibody, Shanghai, 201203, P.R. China.
authors: Weizhu
authors: W
authors: Qian
authors: International Joint Cancer Institute & Translational Medicine Research Institute, the Second Military Medical University, Shanghai, 200433, P.R. China.|Cancer Center, Chinese PLA General Hospital & Chinese PLA Medical School, Beijing, 100853, P.R. China.|National Engineering Research Center for Antibody Medicine and Shanghai Key Laboratory of Cell Engineering & Antibody, Shanghai, 201203, P.R. China.|School of Pharmacy, Liaocheng University, Liaocheng, Shandong, 252000, P.R. China.
authors: Sheng
authors: S
authors: Hou
authors: International Joint Cancer Institute & Translational Medicine Research Institute, the Second Military Medical University, Shanghai, 200433, P.R. China.|Cancer Center, Chinese PLA General Hospital & Chinese PLA Medical School, Beijing, 100853, P.R. China.
authors: Bohua
authors: B
authors: Li
authors: National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing, 100101, P.R. China.|Laboratory of Structural Biology and MOE Laboratory of Protein Science, School of Medicine, Tsinghua University, Beijing, 100084, P.R. China.
authors: Zihe
authors: Z
authors: Rao
authors: Laboratory of Structural Biology and MOE Laboratory of Protein Science, School of Medicine, Tsinghua University, Beijing, 100084, P.R. China.
authors: Zhiyong
authors: Z
authors: Lou
authors: International Joint Cancer Institute & Translational Medicine Research Institute, the Second Military Medical University, Shanghai, 200433, P.R. China.|Cancer Center, Chinese PLA General Hospital & Chinese PLA Medical School, Beijing, 100853, P.R. China.|School of Medicine, Nankai University, Tianjin, 300071, P.R. China.|National Engineering Research Center for Antibody Medicine and Shanghai Key Laboratory of Cell Engineering & Antibody, Shanghai, 201203, P.R. China.|School of Pharmacy, Liaocheng University, Liaocheng, Shandong, 252000, P.R. China.
authors: Yajun
authors: Y
authors: Guo
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D005260:Female; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009857:Oncogenes; D011487:Protein Conformation; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry* / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human
references: FEBS Lett. 2004 Jul 2;569(1-3):332-6
references: 15225657
references: Cell. 2000 Oct 13;103(2):211-25
references: 11057895
references: Ann N Y Acad Sci. 2008;1130:280-6
references: 18596360
references: Mol Cell Biol. 1995 Mar;15(3):1182-91
references: 7532277
references: Mol Cell Biol. 1995 Dec;15(12):6496-505
references: 8524214
references: Nat Rev Mol Cell Biol. 2006 Jul;7(7):505-16
references: 16829981
references: Mol Cell. 2003 Sep;12(3):541-52
references: 14527402
references: Oncogene. 2002 Jan 10;21(2):328
references: 11840330
references: Mol Cell Biol. 1999 Oct;19(10):6845-57
references: 10490623
references: Nature. 2003 Feb 13;421(6924):756-60
references: 12610629
references: MAbs. 2014 Jul-Aug;6(4):978-90
references: 24838231
references: Cell. 2002 Sep 20;110(6):775-87
references: 12297050
references: Mol Cell. 2003 Feb;11(2):495-505
references: 12620236
references: Proc Natl Acad Sci U S A. 1999 Apr 27;96(9):4995-5000
references: 10220407
references: Exp Cell Res. 2003 Mar 10;284(1):31-53
references: 12648464
references: Nature. 2009 Sep 10;461(7261):287-91
references: 19718021
references: Cell. 2010 Aug 20;142(4):568-79
references: 20723758
references: J Cell Sci. 2008 Oct 1;121(Pt 19):3207-17
references: 18782861
references: Nat Rev Mol Cell Biol. 2001 Feb;2(2):127-37
references: 11252954
references: EMBO J. 1996 Jan 15;15(2):254-64
references: 8617201
references: Cancer Cell. 2004 Apr;5(4):317-28
references: 15093539
references: Cell. 2002 Sep 20;110(6):763-73
references: 12297049
references: Cell. 2004 Jan 23;116(2):191-203
references: 14744431
references: J Biol Chem. 1995 Feb 17;270(7):3068-73
references: 7531698
references: Cell. 2002 Sep 20;110(6):669-72
references: 12297041
references: Cancer Cell. 2002 Aug;2(2):127-37
references: 12204533
references: Curr Opin Cell Biol. 2007 Apr;19(2):124-34
references: 17314037
references: FEBS Lett. 1997 Jun 23;410(1):83-6
references: 9247128
references: J Biol Chem. 2002 Aug 9;277(32):28468-73
references: 12000754
references: Diagn Mol Pathol. 2009 Mar;18(1):11-21
references: 19214113