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

Trésaugues L, Silvander C, Flodin S, Welin M, Nyman T, Gräslund S, Hammarström M, Berglund H, Nordlund P

Structure 22 (5) 744-755 [2014-05-06; online 2014-04-08]

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.

Protein Science Facility (PSF)

QC bibliography QC xrefs

PubMed 24704254

DOI 10.1016/j.str.2014.01.013

Crossref 10.1016/j.str.2014.01.013

PDB 3MTC

PDB 3NR9

PDB 3NRS

PDB 4CML

PDB 4CMN

S0969-2126(14)00073-2