The Journal of Experimental Medicine
StemCell Technologies
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Published online 31 January 2005 doi:10.1084/jem.20041890
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 3, 441-452
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ARTICLE

 Structural basis for the function and regulation of the receptor protein tyrosine phosphatase CD45

Hyun-Joo Nam1,2, Florence Poy1, Haruo Saito1,2,3, and Christin A. Frederick1,2

1 Dana-Farber Cancer Institute, Boston, MA 02115
2 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115
3 Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan

CORRESPONDENCE Haruo Saito: h-saito{at}ims.u-tokyo.ac.jp

CD45 is the prototypic member of transmembrane receptor-like protein tyrosine phosphatases (RPTPs) and has essential roles in immune functions. The cytoplasmic region of CD45, like many other RPTPs, contains two homologous protein tyrosine phosphatase domains, active domain 1 (D1) and catalytically impaired domain 2 (D2). Here, we report crystal structure of the cytoplasmic D1D2 segment of human CD45 in native and phosphotyrosyl peptide-bound forms. The tertiary structures of D1 and D2 are very similar, but doubly phosphorylated CD3{zeta} immunoreceptor tyrosine-based activation motif peptide binds only the D1 active site. The D2 "active site" deviates from the other active sites significantly to the extent that excludes any possibility of catalytic activity. The relative orientation of D1 and D2 is very similar to that observed in leukocyte common antigen–related protein with both active sites in an open conformation and is restrained through an extensive network of hydrophobic interactions, hydrogen bonds, and salt bridges. This crystal structure is incompatible with the wedge model previously suggested for CD45 regulation.

H.-J. Nam's present address is Dept. of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL 32610.

Abbreviations used: BNL, Brookhaven National Laboratory; D1, domain 1; D2, domain 2; ITAM, immunoreceptor tyrosine-based activation motif; LAR, leukocyte common antigen–related; PTP, protein tyrosine phosphatase; RPTP, receptor-like PTP; Rsym, R factor for symmetry-related reflections; Sel-Met, selenomethionine.


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