Receptor Linked Protein Tyrosine Phosphotases

Dana-Farber Cancer Institute
posted on 02/05/2009

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Tyrosine phosphorylation is an important molecular switching mechanism that regulates a variety of cellular functions including cell proliferation, differentiation, and activation. Protein tyrosine phosphatases (PTPases) are critically involved in tyrosine phosphorylation; two conserved, intracellular phosphatase domains (D1 and D2) typify the receptor-type PTPases (RPTPases). This technology features methods for determining the three-dimensional structure of members of the RPTPase family. Accordingly, this invention provides the structure of the two domain Leukocyte Common Antigen Related D1/D2 protein (LAR). The invention also provides the structure of the cytoplasmic portion of CD45, the other prototypic member of the RPTPase family (in addition to LAR).

Applications/Advantages: Tyrosine phosphorylation is not only an essential part of signal transduction mediated by various growth factor receptors, but is also involved in intracellular signal transduction and nuclear cell cycle regulation. Disturbances of these processes are known to be causes of cancer. High quality crystallographic data reveals mechanistic information concerning tyrosine phosphorylation that in turn guides rational drug design. This technology provides the first high quality crystals and corresponding structural data concerning the membrane distal PTPase (D2) domain, and structures of the two consecutive PTPase domains within the same polypeptide chain. One may use the atomic coordinates to identify molecules that bind to CD45 and LAR. The crystallization methods for LAR and CD45 may prove especially valuable, as they can potentially be extrapolated to other protein tyrosine phosphatases.