Structural basis for phosphoinositide substrate recognition, catalysis, and membrane interactions in human inositol polyphosphate 5-phosphatases.
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.
Structural Genomics Consortium, Karolinska Institutet, 17177 Stockholm, Sweden.
Lionel
L
Trésaugues
Structural Genomics Consortium, Karolinska Institutet, 17177 Stockholm, Sweden. Electronic address: camilla.silvander@sprintbioscience.com.
Camilla
C
Silvander
Structural Genomics Consortium, Karolinska Institutet, 17177 Stockholm, Sweden.
Susanne
S
Flodin
Structural Genomics Consortium, Karolinska Institutet, 17177 Stockholm, Sweden.
Martin
M
Welin
Structural Genomics Consortium, Karolinska Institutet, 17177 Stockholm, Sweden.
Tomas
T
Nyman
Structural Genomics Consortium, Karolinska Institutet, 17177 Stockholm, Sweden.
Susanne
S
Gräslund
Structural Genomics Consortium, Karolinska Institutet, 17177 Stockholm, Sweden.
Martin
M
Hammarström
Structural Genomics Consortium, Karolinska Institutet, 17177 Stockholm, Sweden.
Helena
H
Berglund
Structural Genomics Consortium, Karolinska Institutet, 17177 Stockholm, Sweden; Division of Biophysics, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden; Centre for Biomedical Structural Biology, School of Biological Sciences, Nanyang Technological University, 637551, Singapore. Electronic address: par.nordlund@ki.se.
Pär
P
Nordlund
D020134:Catalytic Domain; D002462:Cell Membrane / Q000378:metabolism*; D018360:Crystallography, X-Ray; D006801:Humans; D007295:Inositol Phosphates / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010716:Phosphatidylinositols / Q000737:chemistry / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry* / Q000378:metabolism*; D013379:Substrate Specificity; D000099182:Phosphoinositide 5-Phosphatases
D007295:Inositol Phosphates; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010716:Phosphatidylinositols; D010744:Phosphoric Monoester Hydrolases; D000099182:Phosphoinositide 5-Phosphatases; C075695:OCRL protein, human; C098706:INPPL1 protein, human