ArticleJournal of molecular biology2013
Molecular mechanism of membrane binding of the GRP1 PH domain.
Article in Journal of molecular biology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed.
- PI3K Regulates Wild-type RAS Signaling to Confer Resistance to KRAS Inhibition.Cancer research · 2026Article
- Two-step mechanism of Bruton's tyrosine kinase membrane recruitment and activation.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Binding orientation of weakly associating membrane peripheral proteins via membrane paramagnetic relaxation enhancement NMR.Communications chemistry · 2026Article
- Two-Step Mechanism of Bruton's Tyrosine Kinase Membrane Recruitment and Activation.bioRxiv : the preprint server for biology · 2025Article
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- Lysosomal PIPProceedings of the National Academy of Sciences of the United States of America · 2025Article
- The Influence of Phosphoinositide Lipids in the Molecular Biology of Membrane Proteins: Recent Insights from Simulations.Journal of molecular biology · 2025Review
- Small Molecule Modulator of the mTORC2 Pathway Discovered from a DEL Library Designed to Bind to Pleckstrin Homology Domains.ACS chemical biology · 2024Article
- Cooperative Membrane Binding of HIV-1 Matrix Proteins.The journal of physical chemistry. B · 2024Article
- Molecular dynamics simulations of HIV-1 matrix-membrane interactions at different stages of viral maturation.Biophysical journal · 2024Article
- Specific interactions of peripheral membrane proteins with lipids: what can molecular simulations show us?Bioscience reports · 2022Article
- PLEKHA7 signaling is necessary for the growth of mutant KRAS driven colorectal cancer.Experimental cell research · 2021Article
- Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design.Pharmaceuticals (Basel, Switzerland) · 2021Review
- Binding of CaStructure (London, England : 1993) · 2021Article
- CYRI-A limits invasive migration through macropinosome formation and integrin uptake regulation.The Journal of cell biology · 2021Article
- Structural basis for the association of PLEKHA7 with membrane-embedded phosphatidylinositol lipids.Structure (London, England : 1993) · 2021Article
- Flexible pivoting of dynamin pleckstrin homology domain catalyzes fission: insights into molecular degrees of freedom.Molecular biology of the cell · 2021Article
- Capturing Choline-Aromatics Cation-π Interactions in the MARTINI Force Field.Journal of chemical theory and computation · 2020Article
- Microscopic Characterization of GRP1 PH Domain Interaction with Anionic Membranes.Journal of computational chemistry · 2020Article
- The energetics of protein-lipid interactions as viewed by molecular simulations.Biochemical Society transactions · 2020Review
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Authors and funding
6 authors.
Funding
Abstract
The pleckstrin homology (PH) domain of the general receptor of phosphoinositides 1 (GRP1) protein selectively binds to a rare signaling phospholipid, phosphatidylinositol (3,4,5)-trisphosphate (PIP3), in the membrane. The specific PIP3 lipid docking of GRP1 PH domain is essential to protein cellular function and is believed to occur in a stepwise process, electrostatic-driven membrane association followed by the specific PIP3 binding. By a combination of all-atom molecular dynamics (MD) simulations, coarse-grained analysis, electron paramagnetic resonance (EPR) membrane docking geometry, and fluorescence resonance energy transfer (FRET) kinetic studies, we have investigated the search and bind process in the GRP1 PH domain at the molecular scale. We simulated the two membrane binding states of the GRP1 PH domain in the PIP3 search process, before and after the GRP1 PH domain docks with the PIP3 lipid. Our results suggest that the background anionic phosphatidylserine lipids, which constitute around one-fifth of the membrane by composition, play a critical role in the initial stages of recruiting protein to the membrane surface through non-specific electrostatic interactions. Our data also reveal a previously unseen transient membrane association mechanism that is proposed to enable a two-dimensional "hopping" search of the membrane surface for the rare PIP3 target lipid. We further modeled the PIP3-bound membrane-protein system using the EPR membrane docking structure for the MD simulations, quantitatively validating the EPR membrane docking structure and augmenting our understanding of the binding interface with atomic-level detail. Several observations and hypotheses reached from our MD simulations are also supported by experimental kinetic studies.
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