Article
- The EMBO Journal (2009) 28, 1831 - 1842
- doi:10.1038/emboj.2009.155
Published online: 18 June 2009
Subject Categories:
A PH domain within OCRL bridges clathrin-mediated membrane trafficking to phosphoinositide metabolism
Yuxin Mao1,2, Daniel M Balkin1, Roberto Zoncu1, Kai S Erdmann1,a, Livia Tomasini1, Fenghua Hu2, Moonsoo M Jin3, Michael E Hodsdon4 and Pietro De Camilli1,5
- Department of Cell Biology, Howard Hughes Medical Institute, Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University, New Haven, CT, USA
- Weill Institute for Cell and Molecular Biology and Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA
- Department of Biomedical Engineering, Cornell University, Ithaca, NY, USA
- Department of Laboratory Medicine, Yale University, New Haven, CT, USA
- Department of Neurobiology and Kavli Institute for Neuroscience, Yale University, New Haven, CT, USA
Correspondence to:
Michael E Hodsdon, Department of Laboratory Medicine, Yale University, School of Medicine, 789 Howard Avenue, New Haven, CT 06519, USA. Tel.: +1 203 737 2674; Fax: +1 203 688 8704; E-mail: michael.hodsdon@yale.edu
Pietro De Camilli, Department of Cell Biology, Howard Hughes Medical Institute, Yale University, School of Medicine, 295 Congress Avenue, New Haven, CT 06511, USA. Tel.: +1 203 737 4461; Fax: +1 203 737 4436; E-mail: pietro.decamilli@yale.edu
aPresent address: Department of Biochemistry II, Ruhr-University Bochum, Bochum 44780, Germany
Received 4 February 2009; Accepted 13 May 2009
Abstract
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.
Keywords:
- AP-2,
- APPL,
- endocytosis,
- PI(4,5)P2,
- Rab5
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