Molecular analysis of receptor protein tyrosine phosphatase mu-mediated cell adhesion.
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.
Aricescu
Alexandru Radu
AR
Division of Structural Biology, Henry Wellcome Building of Genomic Medicine, University of Oxford, Oxford, UK.
Hon
Wai-Ching
WC
Siebold
Christian
C
Lu
Weixian
W
van der Merwe
Philip Anton
PA
Jones
Edith Yvonne
EY
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
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