Molecular analysis of receptor protein tyrosine phosphatase [mu]-mediated cell adhesion

• Published in: The EMBO journal Vol. 25; no. 4; p. 701
• Main Authors: Alexandru Radu Aricescu, Wai-Ching, Hon, Siebold, Christian, Lu, Weixian, Philip Anton van der Merwe, Jones, Edith Yvonne
• Format: Journal Article
• Language: English
• Published: Heidelberg Blackwell Publishing Ltd 22.02.2006
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/sj.emboj.7600974

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.