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The Journal of Biological Chemistry Jul 2015Cell physiological processes require the regulation and coordination of both mechanical and dynamical properties of the actin cytoskeleton. Here we review recent... (Review)
Review
Cell physiological processes require the regulation and coordination of both mechanical and dynamical properties of the actin cytoskeleton. Here we review recent advances in understanding the mechanical properties and stability of actin filaments and how these properties are manifested at larger (network) length scales. We discuss how forces can influence local biochemical interactions, resulting in the formation of mechanically sensitive dynamic steady states. Understanding the regulation of such force-activated chemistries and dynamic steady states reflects an important challenge for future work that will provide valuable insights as to how the actin cytoskeleton engenders mechanoresponsiveness of living cells.
Topics: Actin Cytoskeleton; Actins; Animals; Biomechanical Phenomena; Humans; Models, Molecular; Protein Structure, Tertiary
PubMed: 25957404
DOI: 10.1074/jbc.R115.636472 -
Biophysical Journal Jan 2022FiberSim is a flexible open-source model of myofilament-level contraction. The code uses a spatially explicit technique, meaning that it tracks the position and status...
FiberSim is a flexible open-source model of myofilament-level contraction. The code uses a spatially explicit technique, meaning that it tracks the position and status of each contractile molecule within the lattice framework. This allows the model to simulate some of the mechanical effects modulated by myosin-binding protein C, as well as the dose dependence of myotropes and the effects of varying isoform expression levels. This paper provides a short introduction to FiberSim and presents simulations of tension-pCa curves with and without regulation of thick and thin filament activation by myosin-binding protein C. A myotrope dose-dependent response as well as slack/re-stretch maneuvers to assess rates of tension recovery are also presented. The software was designed to be flexible (the user can define their own model and/or protocol) and computationally efficient (simulations can be performed on a regular laptop). We hope that other investigators will use FiberSim to explore myofilament level mechanisms and to accelerate research focusing on the contractile properties of sarcomeres.
Topics: Actin Cytoskeleton; Calcium; Muscle Contraction; Myocardial Contraction; Myofibrils; Sarcomeres
PubMed: 34932957
DOI: 10.1016/j.bpj.2021.12.021 -
Biophysical Journal Feb 2013Mathematical modeling has established its value for investigating the interplay of biochemical and mechanical mechanisms underlying actin-based motility. Because of the... (Review)
Review
Mathematical modeling has established its value for investigating the interplay of biochemical and mechanical mechanisms underlying actin-based motility. Because of the complex nature of actin dynamics and its regulation, many of these models are phenomenological or conceptual, providing a general understanding of the physics at play. But the wealth of carefully measured kinetic data on the interactions of many of the players in actin biochemistry cries out for the creation of more detailed and accurate models that could permit investigators to dissect interdependent roles of individual molecular components. Moreover, no human mind can assimilate all of the mechanisms underlying complex protein networks; so an additional benefit of a detailed kinetic model is that the numerous binding proteins, signaling mechanisms, and biochemical reactions can be computationally organized in a fully explicit, accessible, visualizable, and reusable structure. In this review, we will focus on how comprehensive and adaptable modeling allows investigators to explain experimental observations and develop testable hypotheses on the intracellular dynamics of the actin cytoskeleton.
Topics: Actin Cytoskeleton; Actins; Animals; Humans; Microfilament Proteins; Models, Biological
PubMed: 23442903
DOI: 10.1016/j.bpj.2012.12.044 -
Nanoscale Jul 2013Actin remodeling is an area of interest in biology in which correlative microscopy can bring a new way to analyze protein complexes at the nanoscale. Advances in EM,... (Review)
Review
Actin remodeling is an area of interest in biology in which correlative microscopy can bring a new way to analyze protein complexes at the nanoscale. Advances in EM, X-ray diffraction, fluorescence, and single molecule techniques have provided a wealth of information about the modulation of the F-actin structure and its regulation by actin binding proteins (ABPs). Yet, there are technological limitations of these approaches to achieving quantitative molecular level information on the structural and biophysical changes resulting from ABPs interaction with F-actin. Fundamental questions about the actin structure and dynamics and how these determine the function of ABPs remain unanswered. Specifically, how local and long-range structural and conformational changes result in ABPs induced remodeling of F-actin needs to be addressed at the single filament level. Advanced, sensitive and accurate experimental tools for detailed understanding of ABP-actin interactions are much needed. This article discusses the current understanding of nanoscale structural and mechanical modulation of F-actin by ABPs at the single filament level using several correlative microscopic techniques, focusing mainly on results obtained by Atomic Force Microscopy (AFM) analysis of ABP-actin complexes.
Topics: Actin Cytoskeleton; Animals; Humans; Microfilament Proteins; Microscopy, Atomic Force; Multiprotein Complexes; Portraits as Topic
PubMed: 23727693
DOI: 10.1039/c3nr01039b -
FEBS Letters Oct 2002Actin, through its various forms of assembly, provides the basic framework for cell motility, cell shape and intracellular organization in all eukaryotic cells. Many... (Review)
Review
Actin, through its various forms of assembly, provides the basic framework for cell motility, cell shape and intracellular organization in all eukaryotic cells. Many other cellular processes, for example endocytosis and cytokinesis, are also associated with dynamic changes of the actin cytoskeleton. Important prerequisites for actin's functional diversity are its intrinsic ability to rapidly assemble and disassemble filaments and its spatially and temporally well-controlled supramolecular organization. A large number of proteins that interact with actin, collectively referred to as actin-binding proteins (ABPs), carefully orchestrate different scenarios. Since its isolation in 1994 [Machesky, L.M. et al. (1994) J. Cell Biol. 127, 107-115], the Arp2/3 complex containing the actin-related proteins Arp2 and Arp3 has evolved to be one of the main players in the assembly and maintenance of many actin-based structures in the cell (for review see [Borths, E.L. and Welch, M.D. (2002) Structure 10, 131-135; May, R.C. (2001) Cell Mol. Life Sci. 58, 1607-1626; Pollard, T.D. et al. (2000) Rev. Biophys. Biomol. Struct. 29, 545-576; Welch, M.D. (1999) Trends Cell Biol. 11, 423-427]). In particular, when it comes to the assembly of the intricate branched actin network at the leading edge of lamellipodia, the Arp2/3 complex seems to have received all the attention in recent years. In parallel, but not so much in the spotlight, several reports showed that actin on its own can assume different conformations [Bubb, M.R. et al. (2002) J. Biol. Chem. 277, 20999-21006; Schoenenberger, C.-A. et al. (1999) Microsc. Res. Tech. 47, 38-50; Steinmetz, M.O. et al. (1998) J. Mol. Biol. 278, 793-811; Steinmetz, M.O. et al. (1997) J. Cell Biol. 138, 559-574; Millonig, R., Salvo, H. and Aebi, U. (1988) J. Cell Biol. 106, 785-796] through which it drives its supramolecular patterning, and which ultimately generate its functional diversity.
Topics: Actin Cytoskeleton; Actins; Animals; Cell Nucleus; Cross-Linking Reagents; Dimerization
PubMed: 12354608
DOI: 10.1016/s0014-5793(02)03267-2 -
The Journal of Physiology Sep 2012This review focuses on the vascular smooth muscle cells present in the medial layer of the blood vessels wall in the fully differentiated state (dVSMCs). The dVSMC... (Review)
Review
This review focuses on the vascular smooth muscle cells present in the medial layer of the blood vessels wall in the fully differentiated state (dVSMCs). The dVSMC contractile phenotype enables these cells to respond in a highly regulated manner to changes in extracellular stimuli. Through modulation of vascular contractile force and vascular compliance dVSMCs regulate blood pressure and blood flow. The cellular and molecular mechanisms by which vascular smooth muscle contractile functions are regulated are not completely elucidated. Recent studies have documented a critical role for actin polymerization and cytoskeletal dynamics in the regulation of contractile function. Here we will review the current understanding of actin cytoskeletal dynamics and focal adhesion function in dVSMCs in order to better understand actin cytoskeleton connections to the extracellular matrix and the effects of cytoskeletal remodelling on vascular contractility and vascular stiffness in health and disease.
Topics: Actin Cytoskeleton; Actins; Animals; Focal Adhesions; Humans; Molecular Motor Proteins; Muscle Contraction; Myocytes, Smooth Muscle; Protein Multimerization; Vascular Stiffness; Vasoconstriction
PubMed: 22687615
DOI: 10.1113/jphysiol.2012.232306 -
Progress in Molecular Biology and... 2014The actin cytoskeleton is a dynamic structure that constantly undergoes complex reorganization events during many cellular processes. Mathematical models and simulations... (Review)
Review
The actin cytoskeleton is a dynamic structure that constantly undergoes complex reorganization events during many cellular processes. Mathematical models and simulations are powerful tools that can provide insight into the physical mechanisms underlying these processes and make predictions that can be experimentally tested. Representation of the interactions of the actin filaments with the plasma membrane and the movement of the plasma membrane for computation remains a challenge. Here, we provide an overview of the different modeling approaches used to study cytoskeletal dynamics and highlight the differential geometry approach that we have used to implement the interactions between the plasma membrane and the cytoskeleton. Using cell spreading as an example, we demonstrate how this approach is able to successfully capture in simulations, experimentally observed behavior. We provide a perspective on how the differential geometry approach can be used for other biological processes.
Topics: Actin Cytoskeleton; Animals; Cell Movement; Cell Shape; Computer Simulation; Humans; Models, Biological; Signal Transduction
PubMed: 24560144
DOI: 10.1016/B978-0-12-397897-4.00002-4 -
Biophysical Journal May 2016A number of key cell processes rely on specific assemblies of actin filaments, which are all constructed from nearly identical building blocks: the abundant and... (Review)
Review
A number of key cell processes rely on specific assemblies of actin filaments, which are all constructed from nearly identical building blocks: the abundant and extremely conserved actin protein. A central question in the field is to understand how different filament networks can coexist and be regulated. Discoveries in science are often related to technical advances. Here, we focus on the ongoing single filament revolution and discuss how these techniques have greatly contributed to our understanding of actin assembly. In particular, we highlight how they have refined our understanding of the many protein-based regulatory mechanisms that modulate actin assembly. It is now becoming apparent that other factors give filaments a specific identity that determines which proteins will bind to them. We argue that single filament techniques will play an essential role in the coming years as we try to understand the many ways actin filaments can take different flavors and unveil how these flavors modulate the action of regulatory proteins. We discuss different factors known to make actin filaments distinguishable by regulatory proteins and speculate on their possible consequences.
Topics: Actin Cytoskeleton; Animals; In Vitro Techniques
PubMed: 27224479
DOI: 10.1016/j.bpj.2016.04.025 -
International Journal of Molecular... Apr 2021Numerous brain diseases are associated with abnormalities in morphology and density of dendritic spines, small membranous protrusions whose structural geometry... (Review)
Review
Numerous brain diseases are associated with abnormalities in morphology and density of dendritic spines, small membranous protrusions whose structural geometry correlates with the strength of synaptic connections. Thus, the quantitative analysis of dendritic spines remodeling in microscopic images is one of the key elements towards understanding mechanisms of structural neuronal plasticity and bases of brain pathology. In the following article, we review experimental approaches designed to assess quantitative features of dendritic spines under physiological stimuli and in pathological conditions. We compare various methodological pipelines of biological models, sample preparation, data analysis, image acquisition, sample size, and statistical analysis. The methodology and results of relevant experiments are systematically summarized in a tabular form. In particular, we focus on quantitative data regarding the number of animals, cells, dendritic spines, types of studied parameters, size of observed changes, and their statistical significance.
Topics: Actin Cytoskeleton; Animals; Brain Diseases; Dendritic Spines; Disease Models, Animal; Neuronal Plasticity; Synaptic Transmission
PubMed: 33919977
DOI: 10.3390/ijms22084053 -
Cytoskeleton (Hoboken, N.J.) Jul 2012Dendritic spines are the sites of most excitatory synapses in the central nervous system. Recent studies have shown that spines function independently of each other, and... (Review)
Review
Dendritic spines are the sites of most excitatory synapses in the central nervous system. Recent studies have shown that spines function independently of each other, and they are currently the smallest known processing units in the brain. Spines exist in an array of morphologies, and spine structure helps dictate synaptic function. Dendritic spines are rich in actin, and actin rearrangements are critical regulators of spine morphology and density. In this review, we discuss the importance of actin in regulating dendritic spine morphogenesis, and discuss the upstream signal transduction pathways that either foster or inhibit actin polymerization. The understanding of actin regulatory pathways is best conceptualized as a hierarchical network in which molecules function in discrete levels defined by their molecular distance to actin. To this end, we focus on several classes of molecules, including guanine nucleotide exchange factors, small GTPases, small GTPase effectors, and actin binding proteins. We discuss how individual proteins in these molecular classes impact spine morphogenesis, and reveal the biochemical interactions in these networks that are responsible for shaping actin polymerization. Finally, we discuss the importance of these actin regulatory pathways in neuropsychiatric disorders.
Topics: Actin Cytoskeleton; Animals; Dendritic Spines; Humans; Signal Transduction
PubMed: 22307832
DOI: 10.1002/cm.21015