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

• 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

SummarySHIP2, 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.

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