title: Crystal Structure and Substrate Specificity of PTPN12.
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.
authors.affiliation: 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.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Molecular Biology and Biochemistry, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong 250012, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Xiao
authors.affiliation: Qilu Hospital, Shandong University, 107 Wenhua Xi Road, Jinan, Shandong 250012, China.
authors.forename: Yunfei
authors.initials: Y
authors.lastname: Xu
authors.affiliation: 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.
authors.forename: Zonglai
authors.initials: Z
authors.lastname: Liang
authors.affiliation: Department of Molecular Biology and Biochemistry, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong 250012, China.
authors.forename: Chuan
authors.initials: C
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Wenshuai
authors.initials: W
authors.lastname: Zheng
authors.affiliation: 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.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Ma
authors.affiliation: 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.
authors.forename: Dongfang
authors.initials: D
authors.lastname: He
authors.affiliation: 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.
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Song
authors.affiliation: Department of Molecular Biology and Biochemistry, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong 250012, China.
authors.forename: Fuai
authors.initials: F
authors.lastname: Cui
authors.affiliation: School of Life Science, Shandong University, Jinan, Shandong 250100, China.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong 250012, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Yi
authors.affiliation: Department of Molecular Biology and Biochemistry, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong 250012, China. Electronic address: sunjinpeng@sdu.edu.cn.
authors.forename: Jin-Peng
authors.initials: JP
authors.lastname: Sun
authors.affiliation: 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: yuxiao@sdu.edu.cn.
authors.forename: Xiao
authors.initials: X
authors.lastname: Yu
mesh_terms: D000595:Amino Acid Sequence; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D017433:Protein Structure, Secondary; D054594:Protein Tyrosine Phosphatase, Non-Receptor Type 12 / Q000737:chemistry* / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D010455:Peptides; D010768:Phosphoserine; D051357:Cyclin-Dependent Kinase 2; C516738:PTPN12 protein, human; D054594:Protein Tyrosine Phosphatase, Non-Receptor Type 12