Disease-causing SAP mutants are defective in ligand binding and protein folding.


Abstract

The X-linked lymphoproliferative (XLP) syndrome is caused by mutations or deletions in the SH2D1A gene that encodes an SH2 domain protein named SH2D1A or SAP. The identification of a number of missense mutations within the protein's SH2 domain, each of which can directly cause disease, provides a unique opportunity to investigate the function of an interaction protein module, SH2, in the pathogenesis of XLP. We show here that SAP mutants found in XLP patients are defective in binding its physiological ligands signaling lymphocyte activating molecule (SLAM), a co-receptor in T cell activation, and Fyn, a Src family protein tyrosine kinase. Consequently, these mutants are deficient in signaling through the SLAM receptor. This is reflected by compromised abilities for the mutants to recruit Fyn to SLAM and to activate Fyn, by reduced phosphorylation of the receptor, and by deficiencies for the mutants in blocking binding of SHP-2 to SLAM. Furthermore, all mutants examined are defective in protein folding as manifested by their significantly reduced melting temperatures upon thermal denaturation, compared to that of SAP. Taken together, these results suggest that defects in ligand binding, receptor signaling, and protein folding collectively contribute to the loss of function for disease-causing SAP mutants. Study holds ProTherm entries: 17506, 17507, 17508, 17509, 17510, 17511, 17512 Extra Details: missense mutations; disease; signaling lymphocyte activating molecule; receptor signaling

Submission Details

ID: RMBmotcP3

Submitter: Connie Wang

Submission Date: April 24, 2018, 8:49 p.m.

Version: 1

Publication Details
Li C;Iosef C;Jia CY;Gkourasas T;Han VK;Shun-Cheng Li S,Biochemistry (2003) Disease-causing SAP mutants are defective in ligand binding and protein folding. PMID:14674764
Additional Information

Structure view and single mutant data analysis

Study data

No weblogo for data of varying length.
Colors: D E R H K S T N Q A V I L M F Y W C G P
 

Data Distribution

Studies with similar sequences (approximate matches)

Correlation with other assays (exact sequence matches)


Relevant PDB Entries

Structure ID Release Date Resolution Structure Title
1KA7 2001-11-07 SAP/SH2D1A bound to peptide n-Y-c
1KA6 2001-11-07 SAP/SH2D1A bound to peptide n-pY
1D4T 1999-10-14 1.1 CRYSTAL STRUCTURE OF THE XLP PROTEIN SAP IN COMPLEX WITH A SLAM PEPTIDE
1D1Z 1999-10-13 1.4 CRYSTAL STRUCTURE OF THE XLP PROTEIN SAP
1D4W 1999-10-14 1.8 CRYSTAL STRUCTURE OF THE XLP PROTEIN SAP IN COMPLEX WITH SLAM PHOSPHOPEPTIDE
1M27 2003-05-06 2.5 Crystal structure of SAP/FynSH3/SLAM ternary complex

Relevant UniProtKB Entries

Percent Identity Matching Chains Protein Accession Entry Name
92.2 A SH2 domain-containing protein 1A Q06AA1 SH21A_PIG
93.8 A SH2 domain-containing protein 1A Q3ZBB1 SH21A_BOVIN
98.4 A SH2 domain-containing protein 1A Q9BG88 SH21A_SAGOE
100.0 A SH2 domain-containing protein 1A Q71S10 SH21A_MACMU
100.0 A SH2 domain-containing protein 1A O60880 SH21A_HUMAN