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PROTEIN STRUCTURE REPORT

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

Structural Genomics Consortium, University of Oxford, Botnar Research Centre, Oxford OX3 7LD, United Kingdom

(RECEIVED February 1, 2006; FINAL REVISION February 1, 2006; ACCEPTED February 22, 2006)

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 is a member of the R2A/IIb subfamily of RPTPs along with RPTPµ, RPTP, and RPTP. Here, we have determined the crystal structure of catalytically active, monomeric D1 domain of RPTP at 1.9 Å. Structural comparison with other PTP family members indicates an overall classical PTP architecture of twisted mixed -sheets flanked by -helices, in which the catalytically important WPD loop is in an unhindered open conformation. Though the residues forming the dimeric interface in the RPTPµ structure are all conserved, they are not involved in the protein–protein interaction in RPTP. The N-terminal -strand, formed by x association with y, is conserved only in RPTPs but not in cytosolic PTPs, and this feature is conserved in the RPTP structure forming a -strand. Analytical ultracentrifugation studies show that the presence of reducing agents and higher ionic strength are necessary to maintain RPTP as a monomer. In this family the crystal structure of catalytically active RPTPµ 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 is monomeric in solution and crystal structure.

Keywords: crystal structure; protein tyrosine phosphatase ; RPTP; catalytic phosphatase D1 domain

Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.062128706.

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