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Title: Structural studies of the SLAMF3 receptor and the adaptor protein SAP
Author: Shaikh, Raeesah
ISNI:       0000 0004 9358 3021
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2020
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SLAMF receptors are a family of nine type I transmembrane domains, expressed broadly on hematopoietic cells. SLAMF3 is also expressed on hepatocytes. On their cytoplasmic region, most SLAMF receptors have multiple immunoreceptor tyrosine-based switch motifs (ITSMs), which act as ligands for the SH2 domain adaptor protein SAP. Uniquely for any known SH2 domain protein, SAP is able to bind an unphosphorylated peptide. Upon binding, SAP recruits the protein tyrosine kinase FYN-T to SLAMF and blocks the binding of the SH2 domain protein tyrosine phosphatase SHP-2. Here, we present chemical shift data of a small molecule binding to SAP and the structure of another small molecule able to bind SAP at the phosphotyrosine binding site. On their extracellular region, SLAMF receptors typically have two extracellular IgSF domains, except for SLAMF3, which has four (D1 to D4). All SLAMF receptors, apart from SLAMF2, homodimerise via their extracellular N-terminal IgV-like domain (D1). Here we present the high-resolution crystal structure of SLAMF3 D1. Similar to other known SLAMF N-terminal IgVlike domains, it comprises a two-layered b-sheet, however it appears to associate more strongly than any previously characterised SLAMF dimers. The interface has an area of approximately 810 Å2 and consists of 20 hydrogen bonds and 8 salt bridges, surrounded by a hydrophobic patch. SLAMF3 D2-3 has an atypical distribution of cysteines, which raises the possibility of an interdomain disulphide bond. We have expressed, refolded, crystallised and collected diffraction data of SLAMF3 D2-3, however we have so far been unable to solve the structure by molecular replacement or by sulphur SAD. We suggest that these domains have diverged since the gene duplication event that created them.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: SLAMF receptors ; Protein SAP ; Thesis