Quantum and All-Atom Molecular Dynamics Simulations of Protonation and Divalent Ion Binding to Phosphatidylinositol 4,5-Bisphosphate (PIP2)

Slochower, David R.; Huwe, Peter J.; Bradley, Ryan; Radhakrishnan, Ravi; Janmey, Paul A.

doi:10.1016/j.bpj.2012.11.474

Cited by 27 publications

(13 citation statements)

References 43 publications

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“…Because elongating root hair tips are preferential sites of Ca 2+ influx and direct interaction of Ca 2+ with PtdIns(4,5)P 2 is known to compete with protein binding to this phosphoinositide ( Levental et al. , 2009 ; Slochower et al. , 2013 ; Shi et al.…”

Section: Resultsmentioning

confidence: 99%

Sec14-nodulin proteins and the patterning of phosphoinositide landmarks for developmental control of membrane morphogenesis

Ghosh

Campos

Huang

et al. 2015

MBoC

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Section: Resultsmentioning

confidence: 99%

Sec14-nodulin proteins and the patterning of phosphoinositide landmarks for developmental control of membrane morphogenesis

Ghosh

Campos

Huang

et al. 2015

MBoC

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“…However, unlike PIP2, the interaction with PS is not fully reversed upon addition of saturating amounts of Ca 2+ . This could be due to differences in binding sites and stoichiometry of the two lipids with Ca 2+ ions (50,51). Interestingly, PS did not promote dimerization, and the tryptophan fluorescence changes were larger.…”

Section: Discussionmentioning

confidence: 96%

PIP2 promotes conformation-specific dimerization of the EphA2 membrane region

Stefanski

Russell

Westerfield

et al. 2021

Journal of Biological Chemistry

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The impact of the EphA2 receptor on cancer malignancy hinges on the two different ways it can be activated. EphA2 induces antioncogenic signaling after ligand binding, but ligand-independent activation of EphA2 is pro-oncogenic. It is believed that the transmembrane (TM) domain of EphA2 adopts two alternate conformations in the ligand-dependent and the ligand-independent states. However, it is poorly understood how the difference in TM helical crossing angles found in the two conformations impacts the activity and regulation of EphA2. We devised a method that uses hydrophobic matching to stabilize two conformations of a peptide comprising the EphA2 TM domain and a portion of the intracellular juxtamembrane (JM) segment. The two conformations exhibit different TM crossing angles, resembling the ligand-dependent and ligand-independent states. We developed a single-molecule technique using styrene maleic acid lipid particles to measure dimerization in membranes. We observed that the signaling lipid PIP 2 promotes TM dimerization, but only in the small crossing angle state, which we propose corresponds to the ligand-independent conformation. In this state the two TMs are almost parallel, and the positively charged JM segments are expected to be close to each other, causing electrostatic repulsion. The mechanism PIP 2 uses to promote dimerization might involve alleviating this repulsion due to its high density of negative charges. Our data reveal a conformational coupling between the TM and JM regions and suggest that PIP 2 might directly exert a regulatory effect on EphA2 activation in cells that is specific to the ligand-independent conformation of the receptor.

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“…A different type of PIP2 cluster is based on divalent metal ions Ca 2þ or Mg 2þ bridging headgroup phosphates (18,19,(23)(24)(25)(26)(27). Complementing these experimental approaches, molecular dynamics simulations also showed that Ca 2þ altered PIP2 properties and induced PIP2 cluster formation (28,29). Some evidence suggests that PIP2 cluster formation also occurs in cells or in unfixed (30,31) or rapidly frozen (32) membrane sheets prepared from cells.…”

Section: Introductionmentioning

confidence: 99%

Multivalent Cation-Bridged PI(4,5)P2 Clusters Form at Very Low Concentrations

Wen

Vogt

Feigenson

2018

Biophysical Journal

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Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P or PIP2), is a key component of the inner leaflet of the plasma membrane in eukaryotic cells. In model membranes, PIP2 has been reported to form clusters, but whether these locally different conditions could give rise to distinct pools of unclustered and clustered PIP2 is unclear. By use of both fluorescence self-quenching and Förster resonance energy transfer assays, we have discovered that PIP2 self-associates at remarkably low concentrations starting below 0.05 mol% of total lipids. Formation of these clusters was dependent on physiological divalent metal ions, such as Ca, Mg, Zn, or trivalent ions Fe and Al. Formation of PIP2 clusters was also headgroup-specific, being largely independent of the type of acyl chain. The similarly labeled phospholipids phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol exhibited no such clustering. However, six phosphoinositide species coclustered with PIP2. The degree of PIP2 cation clustering was significantly influenced by the composition of the surrounding lipids, with cholesterol and phosphatidylinositol enhancing this behavior. We propose that PIP2 cation-bridged cluster formation, which might be similar to micelle formation, can be used as a physical model for what could be distinct pools of PIP2 in biological membranes. To our knowledge, this study provides the first evidence of PIP2 forming clusters at such low concentrations. The property of PIP2 to form such clusters at such extremely low concentrations in model membranes reveals, to our knowledge, a new behavior of PIP2 proposed to occur in cells, in which local multivalent metal ions, lipid compositions, and various binding proteins could greatly influence PIP2 properties. In turn, these different pools of PIP2 could further regulate cellular events.

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Quantum and All-Atom Molecular Dynamics Simulations of Protonation and Divalent Ion Binding to Phosphatidylinositol 4,5-Bisphosphate (PIP2)

Cited by 27 publications

References 43 publications

Sec14-nodulin proteins and the patterning of phosphoinositide landmarks for developmental control of membrane morphogenesis

Sec14-nodulin proteins and the patterning of phosphoinositide landmarks for developmental control of membrane morphogenesis

PIP2 promotes conformation-specific dimerization of the EphA2 membrane region

Multivalent Cation-Bridged PI(4,5)P2 Clusters Form at Very Low Concentrations

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