Structural basis for phosphoinositide substrate recognition, catalysis, and membrane interactions in human inositol polyphosphate 5-phosphatases

Structure. 2014 May 6;22(5):744-55. doi: 10.1016/j.str.2014.01.013. Epub 2014 Apr 3.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catalytic Domain
  • Cell Membrane / metabolism*
  • Crystallography, X-Ray
  • Humans
  • Inositol Phosphates / chemistry
  • Inositol Phosphates / metabolism
  • Models, Molecular
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
  • Phosphatidylinositols / chemistry
  • Phosphatidylinositols / metabolism
  • Phosphoric Monoester Hydrolases / chemistry*
  • Phosphoric Monoester Hydrolases / metabolism*
  • Substrate Specificity

Substances

  • Inositol Phosphates
  • Phosphatidylinositols
  • Phosphoric Monoester Hydrolases
  • OCRL protein, human
  • phosphoinositide 5-phosphatase
  • INPPL1 protein, human
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases

Associated data

  • PDB/3MTC
  • PDB/3NR9
  • PDB/3NRS
  • PDB/4CML
  • PDB/4CMN