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PMID: 18471983 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Comprehensive identification of PIP3-regulated PH domains from C. elegans to H. sapiens by model prediction and live imaging.

Molecular cell ·Vol. 30 ·No. 3 ·2008-05-09 ·Pages 381-92

Park WS, Heo WD, Whalen JH, O'Rourke NA, Bryan HM, Meyer T, Teruel MN

Abstract

Phosphoinositide 3-kinase (PI3K) and its product phosphatidylinositol(3,4,5)-trisphosphate (PIP3) control cell growth, migration, and other processes by recruiting proteins with pleckstrin homology (PH) domains and possibly other domains to the plasma membrane (PM). However, previous experimental and structural work with PH domains left conflicting evidence about which ones are PIP3 regulated. Here we used live-cell confocal imaging of 130 YFP-conjugated mouse PH domains and found that 20% translocated to the PM in response to receptor-generated PIP3 production. We developed a recursive-learning algorithm to predict PIP3 regulation of 1200 PH domains from different eukaryotes and validated that it accurately predicts PIP3 regulation. Strikingly, this algorithm showed that PIP3 regulation is specified by amino acids across the PH domain, not just the PIP3-binding pocket, and must have evolved several times independently from PIP3-insensitive ancestral PH domains. Finally, our algorithm and live-cell experiments provide a functional survey of PH domains in different species, showing that PI3K regulation increased from approximately two C. elegans and four Drosophila to 40 vertebrate proteins.

MeSH Terms
Algorithms Amino Acid Sequence Animals Caenorhabditis elegans Caenorhabditis elegans Proteins/chemistry,genetics,metabolism Humans Mice Microscopy, Confocal/methods Models, Molecular Models, Theoretical Molecular Sequence Data NIH 3T3 Cells Phosphatidylinositol 3-Kinases/metabolism Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositol Phosphates/metabolism Phylogeny Protein Binding Protein Conformation Proteome/analysis Recombinant Fusion Proteins/chemistry,classification,genetics,metabolism Sequence Alignment
Chemicals
Caenorhabditis elegans Proteins Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositol Phosphates Proteome Recombinant Fusion Proteins phosphatidylinositol 3,4,5-triphosphate Phosphatidylinositol 3-Kinases
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Park Wei Sun
Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA.
Heo Won Do
Whalen James H
O'Rourke Nancy A
Bryan Heather M
Meyer Tobias
Teruel Mary N
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Article Info
Journal
Molecular cell
Abbr.
Mol Cell
ISSN
1097-4164
DOI
10.1016/j.molcel.2008.04.008
Published
2008-05-09
Pages
381-92
Language
English
Region
United States
NLM ID
9802571
PMCID
PMC3523718
Subset
IM
Grants
NIMH NIH HHS · R01 MH064801 · United States
NIGMS NIH HHS · R01 GM063702 · United States
NIGMS NIH HHS · R01 GM030179-26 · United States
NIGMS NIH HHS · R01 GM030179 · United States
NIGMS NIH HHS · R01 GM030179-27 · United States
NIGMS NIH HHS · GM0653702 · United States
NIMH NIH HHS · MH064801 · United States
External Links
PubMed source DOI: 10.1016/j.molcel.2008.04.008 PMC Full Text View journal details
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