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  • The EMBO Journal (2006) 25, 701 - 712
  • doi:10.1038/sj.emboj.7600974

Published online: 2 February 2006

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

Alexandru Radu Aricescu1,a, Wai-Ching Hon1,ab, Christian Siebold1, Weixian Lu1, Philip Anton van der Merwe2 and Edith Yvonne Jones1

  1. Division of Structural Biology, Henry Wellcome Building of Genomic Medicine, University of Oxford, Oxford, UK
  2. Sir William Dunn School of Pathology, University of Oxford, Oxford, UK

Correspondence to:

Edith Yvonne Jones, CR-UK Receptor Structure Research Group, Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK. Tel.: +44 1865 287546; Fax: +44 1865 287547; E-mail: yvonne@strubi.ox.ac.uk

aThese authors contributed equally to this work

bPresent address: MRC Laboratory for Molecular Biology, Hills Road, Cambridge CB2 2QH, UK

Received 9 August 2005; Accepted 9 January 2006

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 Å 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.

  • Keywords:

    • cell adhesion,
    • MAM domain,
    • receptor protein tyrosine phosphatase,
    • signal transduction,
    • X-ray crystallography