Insights Into the Molecular Mechanisms of Actin Dynamics: A Multiscale Modeling Approach

2011 ◽  
Author(s):  
Tamara C. Bidone ◽  
Marco A. Deriu ◽  
Giacomo Di Benedetto ◽  
Diana Massai ◽  
Umberto Morbiducci
Keyword(s):  
Cell Migration ◽  
Self Assembly ◽  
Molecular Mechanisms ◽  
Atp Hydrolysis ◽  
Multiple Equilibrium ◽  
Actin Dynamics ◽  
Cellular Processes ◽  
Kinetics Of ◽  
Binding Loop ◽  
Conformational Shifts

Actin dynamics, which is at the basis of many fundamental cellular processes as cell migration [1], is governed by the self-assembly and disassembly of actin monomers (G-actin) that, in turn, are determined by the kinetics of ATP hydrolysis and by the local concentrations of Mg2+ and Ca2+ [2]. During cell migration, interactions of the actin filaments (F-actin) with different nucleotide-cation complexes induce local topological rearrangements, because the filament building G-actins undergo conformational shifts between multiple equilibrium states separated by low-energy barriers. For example, the structural rearrangements of the DNase-I binding loop (residues 38–52) in subdomain 2 are driven by ATP hydrolysis and the changes in the conformation of subdomain 4 are induced by the presence of a tightly-bound Mg2+ or Ca2+ ion (Figure 1a). These conformational shifts alter the cross-linking between monomers, varying the contact surfaces among adjacent inter- and intrasubdomains of G-actin, and reflect on the overall properties of F-actin.

scholarly journals Actin-binding protein G (AbpG) participates in modulating the actin cytoskeleton and cell migration in Dictyostelium discoideum

2015 ◽  
Vol 26 (6) ◽  
pp. 1084-1097 ◽  
Author(s):  
Wei-Chi Lin ◽  
Liang-Chen Wang ◽  
Te-Ling Pang ◽  
Mei-Yu Chen
Keyword(s):  
Cell Migration ◽  
Dictyostelium Discoideum ◽  
Molecular Mechanisms ◽  
Binding Protein ◽  
Protein Domain ◽  
Actin Dynamics ◽  
Actin Binding ◽  
Protein G ◽  
Wild Type ◽  
Actin Binding Protein

Cell migration is involved in various physiological and pathogenic events, and the complex underlying molecular mechanisms have not been fully elucidated. The simple eukaryote Dictyostelium discoideum displays chemotactic locomotion in stages of its life cycle. By characterizing a Dictyostelium mutant defective in chemotactic responses, we identified a novel actin-binding protein serving to modulate cell migration and named it actin-binding protein G (AbpG); this 971–amino acid (aa) protein contains an N-terminal type 2 calponin homology (CH2) domain followed by two large coiled-coil regions. In chemoattractant gradients, abpG− cells display normal directional persistence but migrate significantly more slowly than wild-type cells; expressing Flag-AbpG in mutant cells eliminates the motility defect. AbpG is enriched in cortical/lamellipodial regions and colocalizes well with F-actin; aa 401–600 and aa 501–550 fragments of AbpG show the same distribution as full-length AbpG. The aa 501–550 region of AbpG, which is essential for AbpG to localize to lamellipodia and to rescue the phenotype of abpG− cells, is sufficient for binding to F-actin and represents a novel actin-binding protein domain. Compared with wild-type cells, abpG− cells have significantly higher F-actin levels. Collectively our results suggest that AbpG may participate in modulating actin dynamics to optimize cell locomotion.

scholarly journals Mechanosensitive Expression of Lamellipodin Governs Cell Cycle Progression and Intracellular Stiffness

2020 ◽  
Author(s):  
Joseph A. Brazzo ◽  
Kwonmoo Lee ◽  
Yongho Bae
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Migration ◽  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Cycle Progression ◽  
Cellular Processes ◽  
M Phase ◽  
And Migration ◽  
In Cells

SUMMARYCells exhibit pathological behaviors in response to increased extracellular matrix (ECM) stiffness, including accelerated cell proliferation and migration [1–9], which are correlated with increased intracellular stiffness and tension [2, 3, 10–12]. The biomechanical signal transduction of ECM stiffness into relevant molecular signals and resultant cellular processes is mediated through multiple proteins associated with the actin cytoskeleton in lamellipodia [2, 3, 10, 11, 13]. However, the molecular mechanisms by which lamellipodial dynamics regulate cellular responses to ECM stiffening remain unclear. Previous work described that lamellipodin, a phosphoinositide- and actin filament-binding protein that is known mostly for controlling cell migration [14–21], promotes ECM stiffness-mediated early cell cycle progression [2], revealing a potential commonality between the mechanisms controlling stiffness-dependent cell migration and those controlling cell proliferation. However, i) whether and how ECM stiffness affects the levels of lamellipodin expression and ii) whether stiffness-mediated lamellipodin expression is required throughout cell cycle progression and for intracellular stiffness have not been explored. Here, we show that the levels of lamellipodin expression in cells are significantly increased by a stiff ECM and that this stiffness-mediated lamellipodin upregulation persistently stimulates cell cycle progression and intracellular stiffness throughout the cell cycle, from the early G1 phase to M phase. Finally, we show that both Rac activation and intracellular stiffening are required for the mechanosensitive induction of lamellipodin. More specifically, inhibiting Rac1 activation in cells on stiff ECM reduces the levels of lamellipodin expression, and this effect is reversed by the overexpression of activated Rac1 in cells on soft ECM. We thus propose that lamellipodin is a critical molecular lynchpin in the control of mechanosensitive cell cycle progression and intracellular stiffness.

scholarly journals Theory of Allosteric Regulation in Hsp70 Molecular Chaperones

QRB Discovery ◽  
2020 ◽  
Vol 1 ◽  
Author(s):  
Wayne A. Hendrickson
Keyword(s):  
Molecular Chaperones ◽  
Atp Hydrolysis ◽  
Binding Domain ◽  
Substrate Affinity ◽  
Peptide Substrates ◽  
Cellular Processes ◽  
Slow Kinetics ◽  
Shock Proteins ◽  
Kinetics Of ◽  
Substrate Binding Domain

AbstractHeat-shock proteins of 70 kDa (Hsp70s) are ubiquitous molecular chaperones that function in protein folding as well as other vital cellular processes. They bind and hydrolyze ATP in a nucleotide-binding domain (NBD) to control the binding and release of client polypeptides in a substrate-binding domain (SBD). However, the molecular mechanism for this allosteric action has remained unclear. Here, we develop and experimentally quantify a theoretical model for Hsp70 allostery based on equilibria among Hsp70 conformational states. We postulate that, when bound to ATP, Hsp70 is in equilibrium between a restraining state (R) that restricts ATP hydrolysis and binds peptides poorly, if at all, and a stimulating state (S) that hydrolyzes ATP relatively rapidly and has high intrinsic substrate affinity but rapid binding kinetics; after the hydrolysis to ADP, NBD and SBD disengage into an uncoupled state (U) that binds peptide substrates tightly, but now with slow kinetics of exchange.

scholarly journals Effect of Surface Roughness on Aggregation of Polypeptide Chains: A Monte Carlo Study

Biomolecules ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 596
Author(s):  
Nguyen Truong Co ◽  
Mai Suan Li
Keyword(s):  
Surface Roughness ◽  
Self Assembly ◽  
Molecular Mechanisms ◽  
Monte Carlo Study ◽  
The Self ◽  
Living Organisms ◽  
Polypeptide Chains ◽  
The Impact ◽  
Kinetics Of

The self-assembly of amyloidogenic peptides and proteins into fibrillar structures has been intensively studied for several decades, because it seems to be associated with a number of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease. Therefore, understanding the molecular mechanisms of this phenomenon is important for identifying an effective therapy for the corresponding diseases. Protein aggregation in living organisms very often takes place on surfaces like membranes and the impact of a surface on this process depends not only on the surface chemistry but also on its topology. Our goal was to develop a simple lattice model for studying the role of surface roughness in the aggregation kinetics of polypeptide chains and the morphology of aggregates. We showed that, consistent with the experiment, an increase in roughness slows down the fibril formation, and this process becomes inhibited at a very highly level of roughness. We predicted a subtle catalytic effect that a slightly rough surface promotes the self-assembly of polypeptide chains but does not delay it. This effect occurs when the interaction between the surface and polypeptide chains is moderate and can be explained by taking into account the competition between energy and entropy factors.

scholarly journals N-terminal modification of actin by acetylation and arginylation determines the architecture and assembly rate of linear and branched actin networks

2020 ◽  
Author(s):  
Samantha M. Chin ◽  
Tomoyuki Hatano ◽  
Lavanya Sivashanmugam ◽  
Andrejus Suchenko ◽  
Anna S. Kashina ◽  
...  
Keyword(s):  
Cell Migration ◽  
Binding Proteins ◽  
Molecular Mechanisms ◽  
Leading Edge ◽  
Actin Dynamics ◽  
Actin Binding ◽  
Actin Network ◽  
Post Translational Modification ◽  
Actin Binding Proteins ◽  
N Terminus

AbstractThe great diversity in actin network architectures and dynamics is exploited by cells to drive fundamental biological processes, including cell migration, endocytosis and cell division. While it is known that this versatility is the result of the many actin-remodeling activities of actin-binding proteins, recent work implicates post-translational modification of the actin N-terminus by either acetylation or arginylation itself as an equally important regulatory mechanism. However, the molecular mechanisms by which acetylation and arginylation alter the properties of actin are not well understood. Here, we directly compare how processing, and modification of the N-terminus of actin affects its intrinsic polymerization dynamics and its remodeling by actin-binding proteins that are essential for cell migration. We find that in comparison to acetylated actin, arginylated actin reduces intrinsic as well as formin-mediated elongation and Arp2/3-mediated nucleation. By contrast, there are no significant differences in Cofilin-mediated severing. Taken together, these results suggest that cells can employ the differently modified actins to precisely regulate actin dynamics. In addition, unprocessed, or non-acetylated actin show very different effects on formin-mediated-elongation, Arp2/3-mediated nucleation, and severing by Cofilin. Altogether, this study shows that the nature of the N-terminus of actin can induce distinct actin network dynamics, which can be differentially used by cells to locally finetune actin dynamics at distinct cellular locations, such as at the leading edge.

scholarly journals A molecular model of the surface-assisted protein aggregation process

2018 ◽  
Author(s):  
Y.G. Pan ◽  
S. Banerjee ◽  
K. Zagorski ◽  
L.S. Shlyakhtenko ◽  
A.B. Kolomeisky ◽  
...  
Keyword(s):  
Self Assembly ◽  
Molecular Mechanisms ◽  
Molecular Model ◽  
Critical Role ◽  
Experimental Studies ◽  
Cytosine Deaminase ◽  
Aggregation Process ◽  
Amyloidogenic Proteins ◽  
Low Concentrations ◽  
Kinetics Of

AbstractThe importance of cell surfaces in the self-assembly of proteins is widely accepted. One biologically significant event is the assembly of amyloidogenic proteins into aggregates, which leads to neurodegenerative disorders like Alzheimer’s and Parkinson’s. The interaction of amyloidogenic proteins with cellular membranes appears to dramatically facilitate the aggregation process. Recent findings indicate that, in the presence of surfaces, aggregation occurs at physiologically low concentrations, suggesting interaction with surfaces plays a critical role in the disease-prone aggregation process. However, the molecular mechanisms behind on-surface aggregation remain unclear. Here we provide a theoretical model that offers a molecular explanation. According to this model, monomers transiently immobilized to surfaces increase the local monomer protein concentration and thus work as nuclei to dramatically accelerate the entire aggregation process. This theory was verified by experimental studies, using mica surfaces, to examine the aggregation kinetics of amyloidogenic-synuclein protein (α-Syn) and non-amyloidogenic cytosine deaminase APOBEC3G (A3G).

scholarly journals RhoD regulates cytoskeletal dynamics via the actin nucleation–promoting factor WASp homologue associated with actin Golgi membranes and microtubules

2012 ◽  
Vol 23 (24) ◽  
pp. 4807-4819 ◽  
Author(s):  
Annica K. B. Gad ◽  
Vishal Nehru ◽  
Aino Ruusala ◽  
Pontus Aspenström
Keyword(s):  
Cell Migration ◽  
Actin Filament ◽  
Rho Gtpases ◽  
Actin Dynamics ◽  
Filamin A ◽  
Actin Nucleation ◽  
Cellular Processes ◽  
Golgi Membranes ◽  
Cytoskeletal Dynamics ◽  
Nucleation Promoting Factor

The Rho GTPases have mainly been studied in association with their roles in the regulation of actin filament organization. These studies have shown that the Rho GTPases are essential for basic cellular processes, such as cell migration, contraction, and division. In this paper, we report that RhoD has a role in the organization of actin dynamics that is distinct from the roles of the better-studied Rho members Cdc42, RhoA, and Rac1. We found that RhoD binds the actin nucleation–promoting factor WASp homologue associated with actin Golgi membranes and microtubules (WHAMM), as well as the related filamin A–binding protein FILIP1. Of these two RhoD-binding proteins, WHAMM was found to bind to the Arp2/3 complex, while FILIP1 bound filamin A. WHAMM was found to act downstream of RhoD in regulating cytoskeletal dynamics. In addition, cells treated with small interfering RNAs for RhoD and WHAMM showed increased cell attachment and decreased cell migration. These major effects on cytoskeletal dynamics indicate that RhoD and its effectors control vital cytoskeleton-driven cellular processes. In agreement with this notion, our data suggest that RhoD coordinates Arp2/3-dependent and FLNa-dependent mechanisms to control the actin filament system, cell adhesion, and cell migration.

In situ Time-Resolved Small-Angle X-ray Scattering Reveals the Formation Kinetics of Polyelectrolyte Complex Micelles

2019 ◽  
Author(s):  
Hao Wu ◽  
Jeffrey Ting ◽  
Siqi Meng ◽  
Matthew Tirrell
Keyword(s):  
Small Angle ◽  
Self Assembly ◽  
Electrostatic Interactions ◽  
Polyelectrolyte Complex ◽  
Time Resolved ◽  
X Ray ◽  
X Ray Scattering ◽  
Kinetics Of ◽  
Ray Scattering

We have directly observed the <i>in situ</i> self-assembly kinetics of polyelectrolyte complex (PEC) micelles by synchrotron time-resolved small-angle X-ray scattering, equipped with a stopped-flow device that provides millisecond temporal resolution. This work has elucidated one general kinetic pathway for the process of PEC micelle formation, which provides useful physical insights for increasing our fundamental understanding of complexation and self-assembly dynamics driven by electrostatic interactions that occur on ultrafast timescales.

A Possible Modulation Mechanism of Intramolecular and Intermolecular Interactions for NCAM Polysialylation and Cell Migration

2019 ◽  
Vol 19 (25) ◽  
pp. 2271-2282 ◽  
Author(s):  
Bo Lu ◽  
Xue-Hui Liu ◽  
Si-Ming Liao ◽  
Zhi-Long Lu ◽  
Dong Chen ◽  
...  
Keyword(s):  
Cell Migration ◽  
Intermolecular Interactions ◽  
Mammalian Cells ◽  
Molecular Mechanisms ◽  
Intramolecular Interaction ◽  
Polysialic Acid ◽  
Tumor Cell Migration ◽  
Neural Cell Adhesion ◽  
Polybasic Domains ◽  
Novel Model

Polysialic acid (polySia) is a novel glycan that posttranslationally modifies neural cell adhesion molecules (NCAMs) in mammalian cells. Up-regulation of polySia-NCAM expression or NCAM polysialylation is associated with tumor cell migration and progression in many metastatic cancers and neurocognition. It has been known that two highly homologous mammalian polysialyltransferases (polySTs), ST8Sia II (STX) and ST8Sia IV (PST), can catalyze polysialylation of NCAM, and two polybasic domains, polybasic region (PBR) and polysialyltransferase domain (PSTD) in polySTs play key roles in affecting polyST activity or NCAM polysialylation. However, the molecular mechanisms of NCAM polysialylation and cell migration are still not entirely clear. In this minireview, the recent research results about the intermolecular interactions between the PBR and NCAM, the PSTD and cytidine monophosphate-sialic acid (CMP-Sia), the PSTD and polySia, and as well as the intramolecular interaction between the PBR and the PSTD within the polyST, are summarized. Based on these cooperative interactions, we have built a novel model of NCAM polysialylation and cell migration mechanisms, which may be helpful to design and develop new polysialyltransferase inhibitors.

scholarly journals Regulation of Rho GTPases by RhoGDIs in Human Cancers

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 1037 ◽  
Author(s):  
Cho ◽  
Kim ◽  
Baek ◽  
Kim ◽  
Lee
Keyword(s):  
Cell Migration ◽  
Cancer Progression ◽  
Anticancer Agents ◽  
Rho Gtpases ◽  
Rho Gtpase ◽  
Regulatory Mechanisms ◽  
Malignant Phenotype ◽  
Cellular Processes ◽  
Human Cancers

Rho GDP dissociation inhibitors (RhoGDIs) play important roles in various cellular processes, including cell migration, adhesion, and proliferation, by regulating the functions of the Rho GTPase family. Dissociation of Rho GTPases from RhoGDIs is necessary for their spatiotemporal activation and is dynamically regulated by several mechanisms, such as phosphorylation, sumoylation, and protein interaction. The expression of RhoGDIs has changed in many human cancers and become associated with the malignant phenotype, including migration, invasion, metastasis, and resistance to anticancer agents. Here, we review how RhoGDIs control the function of Rho GTPases by regulating their spatiotemporal activity and describe the regulatory mechanisms of the dissociation of Rho GTPases from RhoGDIs. We also discuss the role of RhoGDIs in cancer progression and their potential uses for therapeutic intervention.

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