Mechanistic principles underlying regulation of the actin cytoskeleton by phosphoinositides
Open accessAbstract
Significance: Membrane phosphoinositides have emerged as key regulators of the actin cytoskeleton in cell migration, morphogenesis, cytokinesis, and endocytosis. However, the molecular mechanisms by which actin-binding proteins (ABPs) interact with phosphoinositide-rich membranes remain remarkably poorly understood. By applying a combination of biochemical, biophysical, and atomistic molecular dynamics simulation approaches on six central ABPs, we discovered that they employ multivalent electrostatic interactions for membrane binding. Strikingly, our experiments revealed that these proteins display enormous differences in their membrane interaction dynamics and in the ranges of phosphoinositide densities that they sense. These differences precisely correlate with the specific functions of these proteins in cytoskeletal dynamics. These findings uncover molecular principles by which membrane phosphoinositides regulate dynamics and architecture of the actin cytoskeleton in cells.
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N-WASP has high affinity for PI(4,5)P2 and is activated in regions of high PI(4,5)P2 density, activating Arp2/3 to initiate actin nucleation; this is important for cell migration and N-WASP localises at extending lamellipodia.
“N-WASP has a high affinity for PI(4,5)P2, and is activated in regions with a high PI(4,5)P2 density, which in turn activates the actin-related protein 2/3 (Arp2/3) complex to initiate actin nucleation. This is important for cell migration; N-WASP localise at extending lamellipodia which are regions of high PI(4,5)P2 density.”
From Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane (2020) · cites this paper as [91]
The Membranes section reports that N-WASP binding increases with PI(4,5)P2 density, and the Discussion describes relatively high-affinity binding and suggests activation in high-PI(4,5)P2 regions such as lamellipodia (page numbers unavailable). The copy does not establish the stated N-WASP-to-Arp2/3 activation sequence or show that N-WASP localizes at extending lamellipodia; its cellular-localization passage specifically describes lamellipodial accumulation of cofilin-1 and Dia2. (LLM, conf=0.86)
Experimental — accuracy not yet measuredERM family proteins cross-link actin filaments to the cell cortex; they have very high affinity for PI(4,5)P2 and dissociate from the membrane only under extreme circumstances.
“ERM family proteins serve to securely cross-link actin filaments to the cell cortex; they have a very high affinity for PI(4,5)P2 and only dissociates from the membrane under extreme circumstances [14,91].”
From Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane (2020) · cites this paper as [91]
The Discussion identifies ezrin and moesin as cortical actin–plasma membrane linkers and reports stable, high-affinity membrane binding at low PI(4,5)P2 density. The Dynamics of ABP-Membrane Interactions section finds very slow ezrin FERM-domain dissociation, but not dissociation only under extreme circumstances; it reports about 10% fluorescence decay over 60 seconds in its assay. The binding and dissociation measurements concern FERM domains rather than establishing that behavior for every full-length ERM protein. (LLM, conf=0.87)
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Cites
Clathrin-mediated endocytosis in budding yeast
Weinberg, J., & Drubin, D. G. (2012) · Trends in Cell Biology · doi:10.1016/j.tcb.2011.09.001 · Cited by 236 · cited 2× · see citing works
“P of actin filament networks against membranes provides forces for many vital cellular processes, including generation of plasma membrane protrusions in cell migration and morphogenesis, as well as the formation of plasma membrane invaginations in endocytosis (1, 2).”
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Muller, M. P., Jiang, T., Sun, C., Lihan, M., Pant, S., Mahinthichaichan, P., Trifan, A., & Tajkhorshid, E. (2019) · Chemical Reviews · doi:10.1021/acs.chemrev.8b00608 · Cited by 282 · see citing works
Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane
Katan, M., & Cockcroft, S. (2020) · Essays in Biochemistry · doi:10.1042/ebc20200041 · Cited by 176 · see citing works
- Authors
- Senju, Y., Kalimeri, M., Koskela, E. V., Somerharju, P., Zhao, H., Vattulainen, I., & Lappalainen, P.
- Affiliations
- University of Helsinki (FI)
- Tampere University of Technology (FI)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2017-10-09
- Volume
- 114
- Issue
- 43
- Pages
- E8977-E8986
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC5664496
- OpenAlex
- W2761700785
- Cited by
- 118
- References
- 1
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 8 · 2023: 19 · 2022: 18 · 2021: 14 · 2020: 17 · 2019: 15 · 2018: 8 · 2017: 1
- FWCI
- 4.58
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Työväentutkimus Vuosikirja (submittedVersion)
- Funders
- Academy of Finland | Biotieteiden ja Ympäristön Tutkimuksen Toimikunta (272130, 292706)
- EC | FP7 | FP7 Ideas: European Research Council (290974)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- actin cytoskeleton, phosphoinositides, actin-binding proteins, membrane binding, cell migration, cytokinesis, endocytosis, cytoskeletal dynamics, molecular dynamics simulation
- MeSH terms
- Actins, Animals, Biomechanical Phenomena, Cell Membrane, Cloning, Molecular, Cytoskeleton, Melanoma, Microfilament Proteins, Phosphatidylinositols, Cell Line, Tumor, Mice, Static Electricity
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