Document Detail


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.
MedLine Citation:
PMID:  21719704     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Xiao Yu; Ming Chen; Sheng Zhang; Zhi-Hong Yu; Jin-Peng Sun; Lina Wang; Sijiu Liu; Tsuyoshi Imasaki; Yuichiro Takagi; Zhong-Yin Zhang
Related Documents :
24252544 - Scorpion toxins for the reversal of bont-induced paralysis.
9821684 - Pectin methyl esterase from orange fruit: characterization and localization by in-situ ...
10521544 - Cloning and expression of a specific human alpha 1,2-mannosidase that trims man9glcnac2...
15776314 - Molecular cloning and characterization of cdna of penaeidin-like antimicrobial peptide ...
1368024 - Peptide screening.
18060874 - The impact of membrane lipid composition on antimicrobial function of an alpha-helical ...
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-06-30
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  286     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2011 Sep 
Date Detail:
Created Date:  2011-08-29     Completed Date:  2011-10-25     Revised Date:  2013-06-28    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  30526-34     Citation Subset:  IM    
Affiliation:
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Data Bank Information
Bank Name/Acc. No.:
PDB/3OLR;  3OMH
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
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:
CA126937/CA/NCI NIH HHS; CA69202/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
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


Previous Document:  Gonadotropin-regulated testicular RNA helicase (GRTH/DDX25), a negative regulator of luteinizing/cho...
Next Document:  A peroxisome proliferator-activated receptor gamma (PPARgamma)/PPARgamma coactivator 1beta autoregul...