Crystal Structure and Substrate Specificity of PTPN12
Hui Li,
Fan Yang,
Chunhua Liu,
Peng Xiao,
Yunfei Xu,
Zonglai Liang,
Chuan Liu,
Hongmei Wang,
Wenjun Wang,
Wenshuai Zheng,
Wei Zhang,
Xiaoyun Ma,
Dongfang He,
Xiaoyuan Song,
Fuai Cui,
Zhigang Xu,
Fan Yi,
Jin-Peng Sun,
Xiao Yu
Affiliations
Hui Li
Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong 250012, China
Fan Yang
Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong 250012, China
Chunhua Liu
Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong 250012, China
Peng Xiao
Department of Molecular Biology and Biochemistry, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong 250012, China
Yunfei Xu
Qilu Hospital, Shandong University, 107 Wenhua Xi Road, Jinan, Shandong 250012, China
Zonglai Liang
Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong 250012, China
Chuan Liu
Department of Molecular Biology and Biochemistry, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong 250012, China
Hongmei Wang
Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong 250012, China
Wenjun Wang
Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong 250012, China
Wenshuai Zheng
Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong 250012, China
Wei Zhang
Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong 250012, China
Xiaoyun Ma
Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong 250012, China
Dongfang He
Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong 250012, China
Xiaoyuan Song
CAS Key Laboratory of Brain Function and Disease, CAS Center for Excellence in Molecular Cell Science, School of Life Sciences, University of Science and Technology of China, Hefei, 230027 China
Fuai Cui
Department of Molecular Biology and Biochemistry, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong 250012, China
Zhigang Xu
School of Life Science, Shandong University, Jinan, Shandong 250100, China
Fan Yi
Department of Pharmacology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong 250012, China
Jin-Peng Sun
Department of Molecular Biology and Biochemistry, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong 250012, China
Xiao Yu
Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong 250012, China
PTPN12 is an important tumor suppressor that plays critical roles in various physiological processes. However, the molecular basis underlying the substrate specificity of PTPN12 remains uncertain. Here, enzymological and crystallographic studies have enabled us to identify two distinct structural features that are crucial determinants of PTPN12 substrate specificity: the pY+1 site binding pocket and specific basic charged residues along its surface loops. Key structurally plastic regions and specific residues in PTPN12 enabled recognition of different HER2 phosphorylation sites and regulated specific PTPN12 functions. In addition, the structure of PTPN12 revealed a CDK2 phosphorylation site in a specific PTPN12 loop. Taken together, our results not only provide the working mechanisms of PTPN12 for desphosphorylation of its substrates but will also help in designing specific inhibitors of PTPN12.
