PUBLICATION
Mechanism of substrate specificity of phosphatidylinositol phosphate kinases
- Authors
- Muftuoglu, Y., Xue, Y., Gao, X., Wu, D., Ha, Y.
- ID
- ZDB-PUB-160722-7
- Date
- 2016
- Source
- Proceedings of the National Academy of Sciences of the United States of America 113(31): 8711-6 (Journal)
- Registered Authors
- Keywords
- crystallography, lipid kinases, protein engineering, substrate specificity
- MeSH Terms
-
- Animals
- Binding Sites/genetics
- Crystallography, X-Ray
- Models, Molecular
- Phosphatidylinositol Phosphates/chemistry
- Phosphatidylinositol Phosphates/metabolism*
- Phosphatidylinositols/chemistry
- Phosphatidylinositols/metabolism
- Phosphorylation
- Phosphotransferases (Alcohol Group Acceptor)/chemistry
- Phosphotransferases (Alcohol Group Acceptor)/genetics
- Phosphotransferases (Alcohol Group Acceptor)/metabolism*
- Protein Binding
- Protein Domains
- Substrate Specificity
- Zebrafish Proteins/chemistry
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- PubMed
- 27439870 Full text @ Proc. Natl. Acad. Sci. USA
Citation
Muftuoglu, Y., Xue, Y., Gao, X., Wu, D., Ha, Y. (2016) Mechanism of substrate specificity of phosphatidylinositol phosphate kinases. Proceedings of the National Academy of Sciences of the United States of America. 113(31):8711-6.
Abstract
The phosphatidylinositol phosphate kinase (PIPK) family of enzymes is primarily responsible for converting singly phosphorylated phosphatidylinositol derivatives to phosphatidylinositol bisphosphates. As such, these kinases are central to many signaling and membrane trafficking processes in the eukaryotic cell. The three types of phosphatidylinositol phosphate kinases are homologous in sequence but differ in catalytic activities and biological functions. Type I and type II kinases generate phosphatidylinositol 4,5-bisphosphate from phosphatidylinositol 4-phosphate and phosphatidylinositol 5-phosphate, respectively, whereas the type III kinase produces phosphatidylinositol 3,5-bisphosphate from phosphatidylinositol 3-phosphate. Based on crystallographic analysis of the zebrafish type I kinase PIP5Kα, we identified a structural motif unique to the kinase family that serves to recognize the monophosphate on the substrate. Our data indicate that the complex pattern of substrate recognition and phosphorylation results from the interplay between the monophosphate binding site and the specificity loop: the specificity loop functions to recognize different orientations of the inositol ring, whereas residues flanking the phosphate binding Arg244 determine whether phosphatidylinositol 3-phosphate is exclusively bound and phosphorylated at the 5-position. This work provides a thorough picture of how PIPKs achieve their exquisite substrate specificity.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping