CRYSTAL STRUCUTURE STUDIES OF OCRL

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. OCRL was originally identified as the product of the gene responsible for the OculoCerebroRenal syndrome of Lowe. The Lowe syndrome is an X-linked disorder involving congenital cataracts, mental retardation, and renal Fanconi syndrome. OCRL is a multi-domain protein comprising a central inositol 5-phosphatase domain that favours PI(4,5)P2 and PI(3,4,5)P3 as substrates. This domain is flanked at its C-terminal side by an ASH and a catalytically inactive RhoGAP-like domain and an N-terminal PH domain. We recently determined the x-ray structure of the termimal ASH and RhoGAP tandem domains and the NMR structure of the N-terminal PH domian. We are now aimed to determine the structure of OCRL mutants that related to human disease. We have obtained crystals of severl mutants. We expect by determination of the structure of OCRL mutants, we will gain insights on the molecular mechanism of this enzyme.