The crystal structure of human receptor protein tyrosine phosphatase κ phosphatase domain 1

The receptor-type protein tyrosine phosphatases (RPTPs) are integral membrane proteins composed of extracellular adhesion molecule-like domains, a single transmembrane domain, and a cytoplasmic domain. The cytoplasmic domain consists of tandem PTP domains, of which the D1 domain is enzymatically active. RPTP kappa is a member of the R2A/IIb subfamily of RPTPs along with RPTP mu, RPTP rho, and RPTP lambda. Here, we have determined the crystal structure of catalytically active, monomeric D1 domain of RPTP kappa at 1.9 angstrom. Structural comparison with other PTP family members indicates an overall classical PTP architecture of twisted mixed beta-sheets flanked by alpha-helices, in which the catalytically important WPD loop is in an unhindered open conformation. Though the residues forming the dimeric interface in the RPTP mu structure are all conserved, they are not involved in the protein protein interaction in RPTP kappa. The N-terminal beta-strand, formed by beta x association with by, is conserved only in RPTPs but not in cytosolic PTPs, and this feature is conserved in the RPTP kappa structure forming a beta-strand. Analytical ultracentrifugation studies show that the presence of reducing agents and higher ionic strength are necessary to maintain RPTP kappa as a monomer. In this family the crystal structure of catalytically active RPTP mu D1 was solved as a dimer, but the dimerization was proposed to be a consequence of crystallization since the protein was monomeric in solution. In agreement, we show that RPTP kappa is monomeric in solution and crystal structure.