Crystal Structure and Substrate Specificity of PTPN12.

Wenshuai Zheng, Xiao Yu, Jin-Peng Sun, Fan Yi, Zhigang Xu, Fuai Cui, Xiaoyuan Song, Dongfang He, Xiaoyun Ma, Wei Zhang, Hui Li, Wenjun Wang, Hongmei Wang, Chuan Liu, Zonglai Liang, Yunfei Xu, Peng Xiao, Chunhua Liu, Fan Yang

Journal: Cell reports 2017;15(6):1345-58

PMID: 27134172

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Abstract

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.

Address: 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; Department of Molecular Biology and Biochemistry, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong 250012, China.; 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; Department of Physiology, Taishan Medical University, Taian, Shandong 271000, China.; Department of Molecular Biology and Biochemistry, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong 250012, China.; Qilu Hospital, Shandong University, 107 Wenhua Xi Road, Jinan, Shandong 250012, China.; 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.; 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.; School of Life Science, Shandong University, Jinan, Shandong 250100, China.; Department of Pharmacology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong 250012, China.; Department of Molecular Biology and Biochemistry, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong 250012, China. Electronic address: [email protected].; 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. Electronic address: [email protected].

DOI: 10.1016/j.celrep.2016.04.016