title: Molecular analysis of receptor protein tyrosine phosphatase mu-mediated cell adhesion.
abstract: Type IIB receptor protein tyrosine phosphatases (RPTPs) are bi-functional cell surface molecules. Their ectodomains mediate stable, homophilic, cell-adhesive interactions, whereas the intracellular catalytic regions can modulate the phosphorylation state of cadherin/catenin complexes. We describe a systematic investigation of the cell-adhesive properties of the extracellular region of RPTPmu, a prototypical type IIB RPTP. The crystal structure of a construct comprising its N-terminal MAM (meprin/A5/mu) and Ig domains was determined at 2.7 A resolution; this assigns the MAM fold to the jelly-roll family and reveals extensive interactions between the two domains, which form a rigid structural unit. Structure-based site-directed mutagenesis, serial domain deletions and cell-adhesion assays allowed us to identify the four N-terminal domains (MAM, Ig, fibronectin type III (FNIII)-1 and FNIII-2) as a minimal functional unit. Biophysical characterization revealed at least two independent types of homophilic interaction which, taken together, suggest that there is the potential for formation of a complex and possibly ordered array of receptor molecules at cell contact sites.
authors.affiliation: Division of Structural Biology, Henry Wellcome Building of Genomic Medicine, University of Oxford, Oxford, UK.
authors.forename: Alexandru Radu
authors.initials: AR
authors.lastname: Aricescu
authors.forename: Wai-Ching
authors.initials: WC
authors.lastname: Hon
authors.forename: Christian
authors.initials: C
authors.lastname: Siebold
authors.forename: Weixian
authors.initials: W
authors.lastname: Lu
authors.forename: Philip Anton
authors.initials: PA
authors.lastname: van der Merwe
authors.forename: Edith Yvonne
authors.initials: EY
authors.lastname: Jones
mesh_terms: D020134:Catalytic Domain / Q000502:physiology; D002448:Cell Adhesion / Q000502:physiology; D002460:Cell Line; D018360:Crystallography, X-Ray; D005353:Fibronectins / Q000737:chemistry; D006801:Humans; D016297:Mutagenesis, Site-Directed; D017434:Protein Structure, Tertiary / Q000502:physiology; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; D040681:Structural Homology, Protein
chemical_list: D005353:Fibronectins; C501364:fibronectin type III like peptide, human; C516859:PTPRM protein, human; D017027:Protein Tyrosine Phosphatases; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2