Molecular mechanism of membrane binding of the GRP1 PH domain

Chun Liang Lai, Anand Srivastava, Carissa Pilling, Anna R. Chase, Joseph J. Falke, Gregory A. Voth

Research output: Contribution to journalArticle

30 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3073-3090
Number of pages18
JournalJournal of Molecular Biology
Volume425
Issue number17
DOIs
StatePublished - Sep 9 2013
Externally publishedYes

Fingerprint

Membranes
Electron Spin Resonance Spectroscopy
Molecular Dynamics Simulation
Lipids
Static Electricity
Membrane Proteins
phosphatidylinositol receptors
Pleckstrin Homology Domains
Fluorescence Resonance Energy Transfer
Phosphatidylserines
Phospholipids
Proteins

Keywords

  • anionic lipids
  • membrane targeting
  • peripheral membrane protein
  • phosphatidylinositol-3,4,5-trisphosphate or PIP
  • pleckstrin homology domain

ASJC Scopus subject areas

  • Molecular Biology

Cite this

Lai, C. L., Srivastava, A., Pilling, C., Chase, A. R., Falke, J. J., & Voth, G. A. (2013). Molecular mechanism of membrane binding of the GRP1 PH domain. Journal of Molecular Biology, 425(17), 3073-3090. https://doi.org/10.1016/j.jmb.2013.05.026

Molecular mechanism of membrane binding of the GRP1 PH domain. / Lai, Chun Liang; Srivastava, Anand; Pilling, Carissa; Chase, Anna R.; Falke, Joseph J.; Voth, Gregory A.

In: Journal of Molecular Biology, Vol. 425, No. 17, 09.09.2013, p. 3073-3090.

Research output: Contribution to journalArticle

Lai, CL, Srivastava, A, Pilling, C, Chase, AR, Falke, JJ & Voth, GA 2013, 'Molecular mechanism of membrane binding of the GRP1 PH domain', Journal of Molecular Biology, vol. 425, no. 17, pp. 3073-3090. https://doi.org/10.1016/j.jmb.2013.05.026
Lai CL, Srivastava A, Pilling C, Chase AR, Falke JJ, Voth GA. Molecular mechanism of membrane binding of the GRP1 PH domain. Journal of Molecular Biology. 2013 Sep 9;425(17):3073-3090. https://doi.org/10.1016/j.jmb.2013.05.026
Lai, Chun Liang ; Srivastava, Anand ; Pilling, Carissa ; Chase, Anna R. ; Falke, Joseph J. ; Voth, Gregory A. / Molecular mechanism of membrane binding of the GRP1 PH domain. In: Journal of Molecular Biology. 2013 ; Vol. 425, No. 17. pp. 3073-3090.
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