Structural Basis for Phosphoinositide Substrate Recognition, Catalysis, and Membrane Interactions in Human Inositol Polyphosphate 5-Phosphatases

• Published in: Structure (London) Vol. 22; no. 5; pp. 744 - 755
• Main Authors: Trésaugues, Lionel, Silvander, Camilla, Flodin, Susanne, Welin, Martin, Nyman, Tomas, Gräslund, Susanne, Hammarström, Martin, Berglund, Helena, Nordlund, Pär
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.05.2014
• Subjects: Catalytic Domain; Cell Membrane - metabolism; Control; Crystal structure; Crystallography, X-Ray; Human; Humans; Inositol Phosphates - chemistry; Inositol Phosphates - metabolism; Inositols; Lipids; Medicin och hälsovetenskap; Membranes; Models, Molecular; Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; Phosphatidylinositols - chemistry; Phosphatidylinositols - metabolism; Phosphoric Monoester Hydrolases - chemistry; Phosphoric Monoester Hydrolases - metabolism; Polyphosphates; Recognition; Substrate Specificity
• ISSN: 0969-2126; 1878-4186; 1878-4186
• DOI: 10.1016/j.str.2014.01.013

SHIP2, OCRL, and INPP5B belong to inositol polyphosphate 5-phophatase subfamilies involved in insulin regulation and Lowes syndrome. The structural basis for membrane recognition, substrate specificity, and regulation of inositol polyphosphate 5-phophatases is still poorly understood. We determined the crystal structures of human SHIP2, OCRL, and INPP5B, the latter in complex with phosphoinositide substrate analogs, which revealed a membrane interaction patch likely to assist in sequestering substrates from the lipid bilayer. Residues recognizing the 1-phosphate of the substrates are highly conserved among human family members, suggesting similar substrate binding modes. However, 3- and 4-phosphate recognition varies and determines individual substrate specificity profiles. The high conservation of the environment of the scissile 5-phosphate suggests a common reaction geometry for all members of the human 5-phosphatase family. [Display omitted] •Structures of INPP5B/phosphoinositide complexes reveal substrate determinants•Confirmation of the shared catalytic mechanism with AP endonucleases•Determination of the membrane interacting regions•Major differences with the previous model based upon SPsynaptojanin Trésaugues et al. describe structures of apo-OCRL, apo-SHIP2, and INPP5B in complex with product analogs and unravel determinants of substrate selectivity and membrane interacting regions in the phophosinositide 5-phosphatases family. The model suggests a different orientation of the substrate in the active site.