title: A PH domain within OCRL bridges clathrin-mediated membrane trafficking to phosphoinositide metabolism.
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.
authors.affiliation: Department of Cell Biology, Howard Hughes Medical Institute, Yale University, New Haven, CT 06511, USA.
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Mao
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Balkin
authors.forename: Roberto
authors.initials: R
authors.lastname: Zoncu
authors.forename: Kai S
authors.initials: KS
authors.lastname: Erdmann
authors.forename: Livia
authors.initials: L
authors.lastname: Tomasini
authors.forename: Fenghua
authors.initials: F
authors.lastname: Hu
authors.forename: Moonsoo M
authors.initials: MM
authors.lastname: Jin
authors.forename: Michael E
authors.initials: ME
authors.lastname: Hodsdon
authors.forename: Pietro
authors.initials: P
authors.lastname: De Camilli
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002966:Clathrin / Q000737:chemistry / Q000378:metabolism*; D018699:Coated Vesicles / Q000378:metabolism / Q000648:ultrastructure; D004705:Endocytosis; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D019906:Nuclear Magnetic Resonance, Biomolecular; D010716:Phosphatidylinositols / Q000378:metabolism; D010743:Phospholipids; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D051381:Rats; D016415:Sequence Alignment; D000099182:Phosphoinositide 5-Phosphatases
chemical_list: D002966:Clathrin; D010716:Phosphatidylinositols; D010743:Phospholipids; D010744:Phosphoric Monoester Hydrolases; D000099182:Phosphoinositide 5-Phosphatases; C075695:OCRL protein, human