A structural basis for Lowe syndrome caused by mutations in the Rab-binding domain of OCRL1
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A structural basis for Lowe syndrome caused by mutations in the Rab-binding domain of OCRL1. / Hou, Xiaomin; Hagemann, Nina; Schoebel, Stefan; Blankenfeldt, Wulf; Goody, Roger S; Erdmann, Kai S; Itzen, Aymelt.
In: EMBO J, Vol. 30, No. 8, 20.04.2011, p. 1659-70.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - A structural basis for Lowe syndrome caused by mutations in the Rab-binding domain of OCRL1
AU - Hou, Xiaomin
AU - Hagemann, Nina
AU - Schoebel, Stefan
AU - Blankenfeldt, Wulf
AU - Goody, Roger S
AU - Erdmann, Kai S
AU - Itzen, Aymelt
PY - 2011/4/20
Y1 - 2011/4/20
N2 - The oculocerebrorenal syndrome of Lowe (OCRL), also called Lowe syndrome, is characterized by defects of the nervous system, the eye and the kidney. Lowe syndrome is a monogenetic X-linked disease caused by mutations of the inositol-5-phosphatase OCRL1. OCRL1 is a membrane-bound protein recruited to membranes via interaction with a variety of Rab proteins. The structural and kinetic basis of OCRL1 for the recognition of several Rab proteins is unknown. In this study, we report the crystal structure of the Rab-binding domain (RBD) of OCRL1 in complex with Rab8a and the kinetic binding analysis of OCRL1 with several Rab GTPases (Rab1b, Rab5a, Rab6a and Rab8a). In contrast to other effectors that bind their respective Rab predominantly via α-helical structure elements, the Rab-binding interface of OCRL1 consists mainly of the IgG-like β-strand structure of the ASPM-SPD-2-Hydin domain as well as one α-helix. Our results give a deeper structural understanding of disease-causing mutations of OCRL1 affecting Rab binding.
AB - The oculocerebrorenal syndrome of Lowe (OCRL), also called Lowe syndrome, is characterized by defects of the nervous system, the eye and the kidney. Lowe syndrome is a monogenetic X-linked disease caused by mutations of the inositol-5-phosphatase OCRL1. OCRL1 is a membrane-bound protein recruited to membranes via interaction with a variety of Rab proteins. The structural and kinetic basis of OCRL1 for the recognition of several Rab proteins is unknown. In this study, we report the crystal structure of the Rab-binding domain (RBD) of OCRL1 in complex with Rab8a and the kinetic binding analysis of OCRL1 with several Rab GTPases (Rab1b, Rab5a, Rab6a and Rab8a). In contrast to other effectors that bind their respective Rab predominantly via α-helical structure elements, the Rab-binding interface of OCRL1 consists mainly of the IgG-like β-strand structure of the ASPM-SPD-2-Hydin domain as well as one α-helix. Our results give a deeper structural understanding of disease-causing mutations of OCRL1 affecting Rab binding.
KW - Cell Membrane
KW - Crystallization
KW - Crystallography, X-Ray
KW - Fluorescent Antibody Technique
KW - Humans
KW - Immunoprecipitation
KW - Mutation
KW - Oculocerebrorenal Syndrome
KW - Phosphoric Monoester Hydrolases
KW - Protein Conformation
KW - Protein Structure, Tertiary
KW - rab GTP-Binding Proteins
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1038/emboj.2011.60
DO - 10.1038/emboj.2011.60
M3 - SCORING: Journal article
C2 - 21378754
VL - 30
SP - 1659
EP - 1670
JO - EMBO J
JF - EMBO J
SN - 0261-4189
IS - 8
ER -