| 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. | |
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MedLine Citation:
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PMID: 21719704 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Xiao Yu; Ming Chen; Sheng Zhang; Zhi-Hong Yu; Jin-Peng Sun; Lina Wang; Sijiu Liu; Tsuyoshi Imasaki; Yuichiro Takagi; Zhong-Yin Zhang |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2011-06-30 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 286 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2011 Sep |
Date Detail:
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Created Date: 2011-08-29 Completed Date: 2011-10-25 Revised Date: 2012-09-27 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 30526-34 Citation Subset: IM |
Affiliation:
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Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. |
| Data Bank Information | |
Bank Name/Acc. No.:
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PDB/3OLR; 3OMH |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acid Motifs Autoimmunity Cytosol / metabolism Glutathione Transferase / metabolism Humans Intracellular Signaling Peptides and Proteins / chemistry, physiology* Kinetics Models, Molecular Molecular Conformation Mutation, Missense Peptides / chemistry Phosphorylation Protein Binding Protein Tyrosine Phosphatase, Non-Receptor Type 22 / chemistry, physiology* Substrate Specificity src-Family Kinases / metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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CA126937/CA/NCI NIH HHS; CA69202/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Intracellular Signaling Peptides and Proteins; 0/Peptides; 0/src kinase associated phosphoprotein 2; EC 2.5.1.18/Glutathione Transferase; EC 2.7.10.2/src-Family Kinases; EC 3.1.3.48/Protein Tyrosine Phosphatase, Non-Receptor Type 22 |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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