The Structure of the Membrane Distal Phosphatase Domain of RPTPα Reveals Interdomain Flexibility and an SH2 Domain Interaction Region

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Abstract
The receptor protein tyrosine phosphatase α (RPTPα) is a transmembrane receptor with two intracellular protein tyrosine phosphatase domains, a catalytically active membrane proximal domain (D1) and a membrane distal phosphatase domain with minimal catalytic activity (D2). Here we elucidate the crystal structure of RPTPα's D2 domain. Unlike D1, D2 exists as a monomer and lacks the N-terminal inhibitory wedge motif. The N-terminal portion of D2 is disordered, and this region linking D1 to D2 is proteolytically labile in solution whether part of D2 alone or tethered to D1, indicating that the polypeptide backbone of this part of D2 is highly flexible, and therefore accessible to proteases under native conditions. Furthermore, we have crystallized the SH2 domain of the protein tyrosine kinase c-Src, a RPTPα substrate, with a phosphopeptide encompassing the C-terminal phosphorylation site of D2 (pTyr789). The SH2 domain of Src binds RPTPα in an extended conformation. The structural and functional data support a D1−D2 arrangement with significant flexibility between phosphatase domains of RPTPα that is likely to be important for dynamic alterations in intra- and/or intermolecular interactions that are critical for RPTPα function.