Association of Peripheral Membrane Proteins with Membranes: Free Energy of Binding of GRP1 PH Domain with Phosphatidylinositol Phosphate-Containing Model Bilayers

Naughton, Fiona B.; Kalli, Antreas C.; Sansom, Mark S. P.

doi:10.1021/acs.jpclett.6b00153

Cited by 50 publications

(87 citation statements)

References 37 publications

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“…Calculation of free energy profiles for lateral lipid interaction with these sites shows moderately tight binding of CL molecules compared to other regions on the protein, along with clear selectivity for CL over zwitterionic phospholipids, in agreement with indications from 31 P NMR measurements. 11 The well depths for these profiles are −20 to −25 kJ/mol and may be compared to profiles calculated via the same method for other protein–lipid interactions, including interactions of glycolipid and phosphoinositide with the EGFR, 14 binding of phosphoinositide to PH domains, 13 and in particular interactions of CL with mitochondrial C III and C IV . 22,52 This overall suggests the sites on bovine ANT1 have a clear affinity for CL, which is greater than that of the majority of CL binding sites on C IV , and is superseded by only two particularly high-affinity sites on C IV that exhibit interaction free energies of approximately −32 kJ/mol.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, we note the method has previously been shown to correctly predict lipid binding sites on an increasing number of other membrane proteins, 19,21,52 in agreement with experiment, 12 and is capable of predicting the effects of mutation on lipid binding. 13,14 …”

Section: Discussionmentioning

confidence: 99%

“…Multiscale molecular dynamics simulations have proven to be a powerful tool for identifying lipid binding sites 12 and for characterizing the energetics 13−15 and dynamics 16 of the interactions of the lipid with membrane proteins. In this approach, simulations are applied at both coarse-grained (CG) and atomistic resolutions.…”

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confidence: 99%

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Lipid-Loving ANTs: Molecular Simulations of Cardiolipin Interactions and the Organization of the Adenine Nucleotide Translocase in Model Mitochondrial Membranes

et al. 2016

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The exchange of ADP and ATP across the inner mitochondrial membrane is a fundamental cellular process. This exchange is facilitated by the adenine nucleotide translocase, the structure and function of which are critically dependent on the signature phospholipid of mitochondria, cardiolipin (CL). Here we employ multiscale molecular dynamics simulations to investigate CL interactions within a membrane environment. Using simulations at both coarse-grained and atomistic resolutions, we identify three CL binding sites on the translocase, in agreement with those seen in crystal structures and inferred from nuclear magnetic resonance measurements. Characterization of the free energy landscape for lateral lipid interaction via potential of mean force calculations demonstrates the strength of interaction compared to those of binding sites on other mitochondrial membrane proteins, as well as their selectivity for CL over other phospholipids. Extending the analysis to other members of the family, yeast Aac2p and mouse uncoupling protein 2, suggests a degree of conservation. Simulation of large patches of a model mitochondrial membrane containing multiple copies of the translocase shows that CL interactions persist in the presence of protein–protein interactions and suggests CL may mediate interactions between translocases. This study provides a key example of how computational microscopy may be used to shed light on regulatory lipid–protein interactions.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Lipid-Loving ANTs: Molecular Simulations of Cardiolipin Interactions and the Organization of the Adenine Nucleotide Translocase in Model Mitochondrial Membranes

et al. 2016

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“…53 Biophysical and molecular dynamics simulations suggest that the PH domain and the polybasic region bind additional acidic lipids at non-canonical binding sites. 54,55 Whereas the activities and specificities of these 3 subfamilies differ broadly in solution, all are highly potent at activating both Arf1 and Arf6 in the presence of membranes, including EFA6 which is not active on Arf1 in solution. 29,46,49,[56][57][58] These stark differences highlight the importance to assess specificity using membranes and myristoylated Arf GTPases, as this is often the starting point for building models of the biology of the proteins being studied.…”

Section: Regulation Of Ph Domain-containing Arfgefs By Membranesmentioning

confidence: 99%

Allosteric regulation of Arf GTPases and their GEFs at the membrane interface

2016

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Arf GTPases assemble protein complexes on membranes to carry out major functions in cellular traffic. An essential step is their activation by guanine nucleotide exchange factors (GEFs), whose Sec7 domain stimulates GDP/GTP exchange. ArfGEFs form 2 major families: ArfGEFs with DCB, HUS and HDS domains (GBF1 and BIG1/BIG2 in humans), which act at the Golgi; and ArfGEFs with a Cterminal PH domain (cytohesin, EFA6 and BRAG), which function at the plasma membrane and endosomes. In addition, pathogenic bacteria encode an ArfGEF with a unique membrane-binding domain. Here we review the allosteric regulation of Arf GTPases and their GEFs at the membrane interface. Membranes contribute several regulatory layers: at the GTPase level, where activation by GTP is coupled to membrane recruitment by a built-in structural device; at the Sec7 domain, which manipulates this device to ensure that Arf-GTP is attached to membranes; and at the level of noncatalytic ArfGEF domains, which form direct or GTPase-mediated interactions with membranes that enable a spectacular diversity of regulatory regimes. Notably, we show here that membranes increase the efficiency of a large ArfGEF (human BIG1) by 32-fold by interacting directly with its Nterminal DCB and HUS domains. The diversity of allosteric regulatory regimes suggests that ArfGEFs can function in cascades and circuits to modulate the shape, amplitude and duration of Arf signals in cells. Because Arf-like GTPases feature autoinhibitory elements similar to those of Arf GTPases, we propose that their activation also requires allosteric interactions of these elements with membranes or other proteins.

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“…Molecular dynamics (MD) simulations at various resolutions have been used to investigate protein-lipid interactions in PH, [25][26][27][28] C2, [8] and GLA domains [29] and their results optimally complement experimental studies by providing a microscopic view of the lipid-protein interactions determining selectivity and affinity. [30] In the current study, we employ MD simulations to investigate the PIP 3 -specific membrane binding of GRP1-PHD.…”

Section: Introductionmentioning

confidence: 99%

Microscopic Characterization of GRP1 PH Domain Interaction with Anionic Membranes

Pant

Tajkhorshid

2019

J Comput Chem

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The pleckstrin homology (PH) domain of general receptor for phosphoionositides 1 (GRP1-PHD) binds specifically to phosphatidylinositol (3,4,5)-triphosphate (PIP 3 ), and acts as a second messenger. Using an extensive array of molecular dynamics (MD) simulations employing highly mobile membrane mimetic (HMMM) model as well as complementary full membrane simulations, we capture differentiable binding and dynamics of GRP1-PHD in the presence of membranes containing PC, PS, and PIP 3 lipids in varying compositions. While GRP1-PHD forms only transient interactions with pure PC membranes, incorporation of anionic lipids resulted in stable membrane-bound configurations. We report the first observation of two distinct PIP 3 binding modes on GRP1-PHD, involving PIP 3 interactions at a "canonical" and at an "alternate" site, suggesting the possibility of simultaneous binding of multiple anionic lipids. The full membrane simulations confirmed the stability of the membrane bound pose of GRP1-PHD as captured from our HMMM membrane binding simulations. By performing additional steered membrane unbinding simulations and calculating nonequilibrium work associated with the process, as well as metadynamics simulations, on the protein bound to full membranes, allowing for more quantitative examination of the binding strength of the GRP1-PHD to the membrane, we demonstrate that along with the bound PIP 3 , surrounding anionic PS lipids increase the energetic cost of unbinding of GRP1-PHD from the canonical mode, causing them to dissociate more slowly than the alternate mode. Our results demonstrate that concurrent binding of multiple anionic lipids by GRP1-PHD contributes to its membrane affinity, which in turn control its signaling activity.

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Association of Peripheral Membrane Proteins with Membranes: Free Energy of Binding of GRP1 PH Domain with Phosphatidylinositol Phosphate-Containing Model Bilayers

Cited by 50 publications

References 37 publications

Lipid-Loving ANTs: Molecular Simulations of Cardiolipin Interactions and the Organization of the Adenine Nucleotide Translocase in Model Mitochondrial Membranes

Lipid-Loving ANTs: Molecular Simulations of Cardiolipin Interactions and the Organization of the Adenine Nucleotide Translocase in Model Mitochondrial Membranes

Allosteric regulation of Arf GTPases and their GEFs at the membrane interface

Microscopic Characterization of GRP1 PH Domain Interaction with Anionic Membranes

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