title: Substrate specificity of lymphoid-specific tyrosine phosphatase (Lyp) and identification of Src kinase-associated protein of 55 kDa homolog (SKAP-HOM) as a Lyp substrate.
abstract: A missense single-nucleotide polymorphism in the gene encoding the lymphoid-specific tyrosine phosphatase (Lyp) has been identified as a causal factor in a wide spectrum of autoimmune diseases. Interestingly, the autoimmune-predisposing variant of Lyp appears to represent a gain-of-function mutation, implicating Lyp as an attractive target for the development of effective strategies for the treatment of many autoimmune disorders. Unfortunately, the precise biological functions of Lyp in signaling cascades and cellular physiology are poorly understood. Identification and characterization of Lyp substrates will help define the chain of molecular events coupling Lyp dysfunction to diseases. In the current study, we identified consensus sequence motifs for Lyp substrate recognition using an "inverse alanine scanning" combinatorial library approach. The intrinsic sequence specificity data led to the discovery and characterization of SKAP-HOM, a cytosolic adaptor protein required for proper activation of the immune system, as a bona fide Lyp substrate. To determine the molecular basis for Lyp substrate recognition, we solved crystal structures of Lyp in complex with the consensus peptide as well as the phosphopeptide derived from SKAP-HOM. Together with the biochemical data, the structures define the molecular determinants for Lyp substrate specificity and provide a solid foundation upon which novel therapeutics targeting Lyp can be developed for multiple autoimmune diseases.
authors: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors: Xiao
authors: X
authors: Yu
authors: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors: Ming
authors: M
authors: Chen
authors: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors: Sheng
authors: S
authors: Zhang
authors: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors: Zhi-Hong
authors: ZH
authors: Yu
authors: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors: Jin-Peng
authors: JP
authors: Sun
authors: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors: Lina
authors: L
authors: Wang
authors: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors: Sijiu
authors: S
authors: Liu
authors: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors: Tsuyoshi
authors: T
authors: Imasaki
authors: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors: Yuichiro
authors: Y
authors: Takagi
authors: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202. Electronic address: zyzhang@iupui.edu.
authors: Zhong-Yin
authors: ZY
authors: Zhang
mesh_terms: D020816:Amino Acid Motifs; D015551:Autoimmunity; D003600:Cytosol / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000502:physiology*; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D020125:Mutation, Missense; D010455:Peptides / Q000737:chemistry; D010766:Phosphorylation; D011485:Protein Binding; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000737:chemistry / Q000502:physiology*; D013379:Substrate Specificity; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D010455:Peptides; C116431:src kinase associated phosphoprotein 2; D005982:Glutathione Transferase; D019061:src-Family Kinases; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22