Journal
EMBO JOURNAL
Volume 28, Issue 13, Pages 1831-1842Publisher
WILEY
DOI: 10.1038/emboj.2009.155
Keywords
AP-2; APPL; endocytosis; PI(4,5)P-2; Rab5
Categories
Funding
- G Harold and Leila Y Mathers Charitable Foundation
- NIH [NS36251, CA46128, DK45735, DA018343, MSTP TG 5T32GM07205, CA 108992, 1 S10 RR19895]
- Lowe Syndrome Association
- Life Sciences Research Foundation
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OCRL, whose mutations are responsible for Lowe syndrome and Dent disease, and INPP5B are two similar proteins comprising a central inositol 5-phosphatase domain followed by an ASH and a RhoGAP-like domain. Their divergent NH2-terminal portions remain uncharacterized. We show that the NH2-terminal region of OCRL, but not of INPP5B, binds clathrin heavy chain. OCRL, which in contrast to INPP5B visits late stage endocytic clathrin-coated pits, was earlier shown to contain another binding site for clathrin in its COOH-terminal region. NMR structure determination further reveals that despite their primary sequence dissimilarity, the NH2-terminal portions of both OCRL and INPP5B contain a PH domain. The novel clathrin-binding site in OCRL maps to an unusual clathrin-box motif located in a loop of the PH domain, whose mutations reduce recruitment efficiency of OCRL to coated pits. These findings suggest an evolutionary pressure for a specialized function of OCRL in bridging phosphoinositide metabolism to clathrin-dependent membrane trafficking. The EMBO Journal (2009) 28, 1831-1842. doi:10.1038/emboj.2009.155; Published online 18 June 2009
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