Determinants of receptor tyrosine phosphatase homophilic adhesion: structural comparison of PTPRK and PTPRM extracellular domains

DOI: 10.1016/j.jbc.2022.102750

Authors: Iain Hay (University of Cambridge; Babraham Institute) , Maria Shamin (University of Cambridge) , Eve R. Caroe (University of Cambridge) , Ahmed S. A. Mohamed (European Molecular Biology Laboratory (EMBL)) , Dmitri I. Svergun (European Molecular Biology Laboratory (EMBL)) , Cy M. Jeffries (European Molecular Biology Laboratory (EMBL)) , Stephen C. Graham (University of Cambridge) , Hayley J. Sharpe (Babraham Institute) , Janet E. Deane (University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Biological Chemistry , VOL 10

State: Published (Approved)
Published: November 2022
Diamond Proposal Number(s): 15916 , 21426

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.

Journal Keywords: cell adhesion; tyrosine‐protein phosphatase (tyrosine phosphatase); cell contact; receptor structure‐function; X‐ray crystallography; small angle X-ray scattering (SAXS)

Subject Areas: Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography

Added On: 30/11/2022 08:59

Discipline Tags:

Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)