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Instruments / Technical Area	Publication Details	Published	Actions
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	Determinants of receptor tyrosine phosphatase homophilic adhesion: structural comparison of PTPRK and PTPRM extracellular domains Iain Hay , Maria Shamin , Eve R. Caroe , Ahmed S. A. Mohamed , Dmitri I. Svergun , Cy M. Jeffries , Stephen C. Graham , Hayley J. Sharpe , Janet E. Deane Journal Of Biological Chemistry 10 DOI: 10.1016/j.jbc.2022.102750 Diamond Proposal Number(s): [15916, 21426] Open Access Show Abstract ▼ Abstract: The type IIB receptor protein tyrosine phosphatases (R2B RPTPs) are cell surface transmembrane proteins that engage in cell adhesion via their extracellular domains (ECDs) and cell signaling via their cytoplasmic phosphatase domains. The ECDs of R2B RPTPs form stable, homophilic, trans interactions between adjacent cell membranes. Previous work has demonstrated how one family member, PTPRM, forms head-to-tail homodimers. However, as the interface was composed of residues conserved across the family, the determinants of homophilic specificity remain unknown. Here, we have solved the X-ray crystal structure of the membrane-distal, N-terminal domains of PTPRK that form a head-to-tail dimer consistent with intermembrane adhesion. Comparison with the PTPRM structure demonstrates inter-domain conformational differences that may define homophilic specificity. Using small-angle X-ray scattering, we determined the solution structures of the full-length ECDs of PTPRM and PTPRK, identifying that both are rigid, extended molecules that differ in their overall long-range conformation. Furthermore, we identify one residue, W351, within the interaction interface that differs between PTPRM and PTPRK and show that mutation to glycine, the equivalent residue in PTPRM, abolishes PTPRK dimer formation in vitro. This comparison of two members of the receptor tyrosine phosphatase family suggests that homophilic specificity is driven by a combination of shape complementarity and specific but limited sequence differences.	Nov 2022
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	The receptor PTPRU is a redox sensitive pseudophosphatase Iain M. Hay , Gareth W. Fearnley , Pablo Rios , Maja Köhn , Hayley J. Sharpe , Janet E. Deane Nature Communications 11 DOI: 10.1038/s41467-020-17076-w Diamond Proposal Number(s): [15916] Open Access Show Abstract ▼ Abstract: The receptor-linked protein tyrosine phosphatases (RPTPs) are key regulators of cell-cell communication through the control of cellular phosphotyrosine levels. Most human RPTPs possess an extracellular receptor domain and tandem intracellular phosphatase domains: comprising an active membrane proximal (D1) domain and an inactive distal (D2) pseudophosphatase domain. Here we demonstrate that PTPRU is unique amongst the RPTPs in possessing two pseudophosphatase domains. The PTPRU-D1 displays no detectable catalytic activity against a range of phosphorylated substrates and we show that this is due to multiple structural rearrangements that destabilise the active site pocket and block the catalytic cysteine. Upon oxidation, this cysteine forms an intramolecular disulphide bond with a vicinal “backdoor” cysteine, a process thought to reversibly inactivate related phosphatases. Importantly, despite the absence of catalytic activity, PTPRU binds substrates of related phosphatases strongly suggesting that this pseudophosphatase functions in tyrosine phosphorylation by competing with active phosphatases for the binding of substrates.	Jun 2020

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