STRUCTURAL STUDIES OF THE LOWE SYNDROME PROTEIN OCRL

Cornell University, Ithaca NY

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. It is well known that phophoinositides (PIs) play a pivotal role in almost all aspects of cell physiology both as precursors of intracellular second messengers and as regulators of membrane-cytosol interfaces. Phosphoinositide metabolism is tightly regulated by a large number of phosphoinositide metabolizing enzymes, and mutations of several such enzymes are responsible for human disease. Mutations in OCRL (also referred to as INPP5E) cause OculoCerebroRenal Syndrome of Lowe, an X-linked disorder characterized by congenital cataracts, mental retardation, neonatal hypotonia, and renal Fanconi syndrome. Despite many studies of the biochemical properties and cellular functions of OCRL, structural information on this multi-domain enzyme, which is essential for our understanding of its biological functions, is still limited. We successfully crystallized the C-terminal part of OCRL, which contains a novel domain named the ASH domain and a RhoGAP like domain. With the help by the NE-CAT team, we collected an anomalous diffraction data set and solved the structure of the C-terminal part of OCRL. Our crystallographic studies of the COOH-terminal region of OCRL reveal the first structure of a member of the newly defined ASH domain family. Our structure reveals with an unusual clathrin box protruding from a large loop inside the RhoGAP-like domain. Moreover, our structural studies elucidate a potential link between OCRL mutations and the phenotypic manifestations of Lowe syndrome.