title: The family-wide structure and function of human dual-specificity protein phosphatases.
abstract: Dual-specificity protein phosphatases (DUSPs), which dephosphorylate both phosphoserine/threonine and phosphotyrosine, play vital roles in immune activation, brain function and cell-growth signalling. A family-wide structural library of human DUSPs was constructed based on experimental structure determination supplemented with homology modelling. The catalytic domain of each individual DUSP has characteristic features in the active site and in surface-charge distribution, indicating substrate-interaction specificity. The active-site loop-to-strand switch occurs in a subtype-specific manner, indicating that the switch process is necessary for characteristic substrate interactions in the corresponding DUSPs. A comprehensive analysis of the activity-inhibition profile and active-site geometry of DUSPs revealed a novel role of the active-pocket structure in the substrate specificity of DUSPs. A structure-based analysis of redox responses indicated that the additional cysteine residues are important for the protection of enzyme activity. The family-wide structures of DUSPs form a basis for the understanding of phosphorylation-mediated signal transduction and the development of therapeutics.
authors: Medical Proteomics Research Center, KRIBB, Daejeon, Republic of Korea.
authors: Dae Gwin
authors: DG
authors: Jeong
authors: Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Republic of Korea.
authors: Chun Hua
authors: CH
authors: Wei
authors: Medical Proteomics Research Center, KRIBB, Daejeon, Republic of Korea.
authors: Bonsu
authors: B
authors: Ku
authors: Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Republic of Korea.
authors: Tae Jin
authors: TJ
authors: Jeon
authors: Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Republic of Korea.
authors: Pham Ngoc
authors: PN
authors: Chien
authors: Department of Industrial Engineering, College of Engineering, Hanyang University, Seoul, Republic of Korea.
authors: Jae Kwan
authors: JK
authors: Kim
authors: Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Republic of Korea.
authors: So Ya
authors: SY
authors: Park
authors: Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Republic of Korea.
authors: Hyun Sook
authors: HS
authors: Hwang
authors: Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Republic of Korea.
authors: Sun Young
authors: SY
authors: Ryu
authors: Department of Bioscience and Biotechnology, Sejong University, Seoul, Republic of Korea.
authors: Hwangseo
authors: H
authors: Park
authors: Department of Industrial Engineering, College of Engineering, Hanyang University, Seoul, Republic of Korea.
authors: Deok-Soo
authors: DS
authors: Kim
authors: Medical Proteomics Research Center, KRIBB, Daejeon, Republic of Korea.
authors: Seung Jun
authors: SJ
authors: Kim
authors: Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Republic of Korea.
authors: Seong Eon
authors: SE
authors: Ryu
mesh_terms: D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D003545:Cysteine / Q000737:chemistry; D054637:Dual-Specificity Phosphatases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000145:classification* / Q000235:genetics; D004791:Enzyme Inhibitors / Q000737:chemistry*; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D008958:Models, Molecular; D010084:Oxidation-Reduction; D010768:Phosphoserine / Q000737:chemistry; D010769:Phosphothreonine / Q000737:chemistry; D019000:Phosphotyrosine / Q000737:chemistry; D010802:Phylogeny; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000145:classification / Q000235:genetics; D015398:Signal Transduction; D040681:Structural Homology, Protein; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D010769:Phosphothreonine; D010768:Phosphoserine; D019000:Phosphotyrosine; D054637:Dual-Specificity Phosphatases; D003545:Cysteine
keywords: DUSPs; dual-specificity protein phosphatases; protein tyrosine phosphatases