title: Crystal structure of human protein tyrosine phosphatase SHP-1 in the open conformation.
abstract: SHP-1 belongs to the family of non-receptor protein tyrosine phosphatases (PTPs) and generally acts as a negative regulator in a variety of cellular signaling pathways. Previously, the crystal structures of the tail-truncated SHP-1 and SHP-2 revealed an autoinhibitory conformation. To understand the regulatory mechanism of SHP-1, we have determined the crystal structure of the full-length SHP-1 at 3.1 Å. Although the tail was disordered in current structure, the huge conformational rearrangement of the N-SH2 domain and the incorporation of sulfate ions into the ligand-binding site of each domain indicate that the SHP-1 is in the open conformation. The N-SH2 domain in current structure is shifted away from the active site of the PTP domain to the other side of the C-SH2 domain, resulting in exposure of the active site. Meanwhile, the C-SH2 domain is twisted anticlockwise by about 110°. In addition, a set of new interactions between two SH2 domains and between the N-SH2 and the catalytic domains is identified, which could be responsible for the stabilization of SHP-1 in the open conformation. Based on the structural comparison, a model for the activation of SHP-1 is proposed.
authors.affiliation: Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana 70803, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Lijun
authors.initials: L
authors.lastname: Liu
authors.forename: Xi
authors.initials: X
authors.lastname: Song
authors.forename: Yi
authors.initials: Y
authors.lastname: Mo
authors.forename: Chandrasekhar
authors.initials: C
authors.lastname: Komma
authors.forename: Henry D
authors.initials: HD
authors.lastname: Bellamy
authors.forename: Zhizhuang Joe
authors.initials: ZJ
authors.lastname: Zhao
authors.forename: G Wayne
authors.initials: GW
authors.lastname: Zhou
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D004789:Enzyme Activation / Q000502:physiology; D004795:Enzyme Stability; D006801:Humans; D008956:Models, Chemical; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D018909:src Homology Domains
chemical_list: C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6