Substrate specificity and plasticity of FERM-containing protein tyrosine phosphatases.
Epidermal growth factor receptor (EGFR) pathway substrate 15 (Eps15) is a newly identified substrate for protein tyrosine phosphatase N3 (PTPN3), which belongs to the FERM-containing PTP subfamily comprising five members including PTPN3, N4, N13, N14, and N21. We solved the crystal structures of the PTPN3-Eps15 phosphopeptide complex and found that His812 of PTPN3 and Pro850 of Eps15 are responsible for the specific interaction between them. We defined the critical role of the additional residue Tyr676 of PTPN3, which is replaced by Ile939 in PTPN14, in recognition of tyrosine phosphorylated Eps15. The WPD loop necessary for catalysis is present in all members but not PTPN21. We identified that Glu instead of Asp in the WPE loop contributes to the catalytic incapability of PTPN21 due to an extended distance beyond protonation targeting a phosphotyrosine substrate. Together with in vivo validations, our results provide novel insights into the substrate specificity and plasticity of FERM-containing PTPs.
Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.
Kai-En
KE
Chen
Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan; Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei 115, Taiwan.
Meng-Yen
MY
Li
Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan; National Core Facility for Protein Structural Analysis, Academia Sinica, Taipei 115, Taiwan.
Chia-Cheng
CC
Chou
Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.
Meng-Ru
MR
Ho
Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan; Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei 115, Taiwan.
Guang-Chao
GC
Chen
Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan; Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei 115, Taiwan. Electronic address: tcmeng@gate.sinica.edu.tw.
Tzu-Ching
TC
Meng
Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan; Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei 115, Taiwan; National Core Facility for Protein Structural Analysis, Academia Sinica, Taipei 115, Taiwan; Graduate Institute of Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan. Electronic address: ahjwang@gate.sinica.edu.tw.
Andrew H-J
AH
Wang
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001665:Binding Sites; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006801:Humans; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D054589:Protein Tyrosine Phosphatase, Non-Receptor Type 3 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity
D048868:Adaptor Proteins, Signal Transducing; C486206:EPS15 protein, human; C516656:PTPN3 protein, human; D054589:Protein Tyrosine Phosphatase, Non-Receptor Type 3