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Cells Feb 2022Neurons transmit and receive information at specialized junctions called synapses. Excitatory synapses form at the junction between a presynaptic axon terminal and a... (Review)
Review
Neurons transmit and receive information at specialized junctions called synapses. Excitatory synapses form at the junction between a presynaptic axon terminal and a postsynaptic dendritic spine. Supporting the shape and function of these junctions is a complex network of actin filaments and its regulators. Advances in microscopic techniques have enabled studies of the organization of actin at synapses and its dynamic regulation. In addition to highlighting recent advances in the field, we will provide a brief historical perspective of the understanding of synaptic actin at the synapse. We will also highlight key neuronal functions regulated by actin, including organization of proteins in the pre- and post- synaptic compartments and endocytosis of ion channels. We review the evidence that synapses contain distinct actin pools that differ in their localization and dynamic behaviors and discuss key functions for these actin pools. Finally, whole exome sequencing of humans with neurodevelopmental and psychiatric disorders has identified synaptic actin regulators as key disease risk genes. We briefly summarize how genetic variants in these genes impact neurotransmission via their impact on synaptic actin.
Topics: Actin Cytoskeleton; Actins; Humans; Neurons; Synapses; Synaptic Transmission
PubMed: 35203254
DOI: 10.3390/cells11040603 -
Nature Nov 2022ATP-hydrolysis-coupled actin polymerization is a fundamental mechanism of cellular force generation. In turn, force and actin filament (F-actin) nucleotide state...
ATP-hydrolysis-coupled actin polymerization is a fundamental mechanism of cellular force generation. In turn, force and actin filament (F-actin) nucleotide state regulate actin dynamics by tuning F-actin's engagement of actin-binding proteins through mechanisms that are unclear. Here we show that the nucleotide state of actin modulates F-actin structural transitions evoked by bending forces. Cryo-electron microscopy structures of ADP-F-actin and ADP-P-F-actin with sufficient resolution to visualize bound solvent reveal intersubunit interfaces bridged by water molecules that could mediate filament lattice flexibility. Despite extensive ordered solvent differences in the nucleotide cleft, these structures feature nearly identical lattices and essentially indistinguishable protein backbone conformations that are unlikely to be discriminable by actin-binding proteins. We next introduce a machine-learning-enabled pipeline for reconstructing bent filaments, enabling us to visualize both continuous structural variability and side-chain-level detail. Bent F-actin structures reveal rearrangements at intersubunit interfaces characterized by substantial alterations of helical twist and deformations in individual protomers, transitions that are distinct in ADP-F-actin and ADP-P-F-actin. This suggests that phosphate rigidifies actin subunits to alter the bending structural landscape of F-actin. As bending forces evoke nucleotide-state dependent conformational transitions of sufficient magnitude to be detected by actin-binding proteins, we propose that actin nucleotide state can serve as a co-regulator of F-actin mechanical regulation.
Topics: Actin Cytoskeleton; Actins; Adenosine Diphosphate; Cryoelectron Microscopy; Microfilament Proteins; Solvents; Machine Learning; Protein Conformation
PubMed: 36289330
DOI: 10.1038/s41586-022-05366-w -
International Journal of Molecular... Feb 2022Actin-associated proteins (AAPs) act on monomeric globular actin (G-actin) and polymerized filamentous actin (F-actin) to regulate their dynamics and architectures which... (Review)
Review
Actin-associated proteins (AAPs) act on monomeric globular actin (G-actin) and polymerized filamentous actin (F-actin) to regulate their dynamics and architectures which ultimately control cell movement, shape change, division; organelle localization and trafficking. Actin-binding proteins (ABPs) are a subset of AAPs. Since actin was discovered as a myosin-activating protein (hence named actin) in 1942, the protein has also been found to be expressed in non-muscle cells, and numerous AAPs continue to be discovered. This review article lists all of the AAPs discovered so far while also allowing readers to sort the list based on the names, sizes, functions, related human diseases, and the dates of discovery. The list also contains links to the UniProt and Protein Atlas databases for accessing further, related details such as protein structures, associated proteins, subcellular localization, the expression levels in cells and tissues, mutations, and pathology. Because the actin cytoskeleton is involved in many pathological processes such as tumorigenesis, invasion, and developmental diseases, small molecules that target actin and AAPs which hold potential to treat these diseases are also listed.
Topics: Actin Cytoskeleton; Actins; Carcinogenesis; Cell Movement; Humans; Microfilament Proteins; Small Molecule Libraries
PubMed: 35216237
DOI: 10.3390/ijms23042118 -
Biology of the Cell Apr 2023The human immunodeficiency virus type 1 (HIV-1) is an intracellular pathogen whose replication cycle strictly depends on the host cell molecular machinery. HIV-1 crosses... (Review)
Review
The human immunodeficiency virus type 1 (HIV-1) is an intracellular pathogen whose replication cycle strictly depends on the host cell molecular machinery. HIV-1 crosses twice the plasma membrane, to get in and to get out of the cell. Therefore, the first and the last line of intracellular component encountered by the virus is the cortical actin network. Here, we review the role of actin and actin-related proteins in HIV-1 entry, assembly, budding, and release. We first highlight the mechanisms controlling actin polymerization at the entry site that promote the clustering of HIV-1 receptors, a crucial step for the virus to fuse with the plasma membrane. Then, we describe how actin is transiently depolymerized locally to allow the capsid to cross the actin cortex, before migrating towards the nucleus. Finally, we review the role of several actin-binding proteins in actin remodeling events required for membrane deformation and curvature at the viral assembly site as well as for virus release. Strikingly, it appears that common actin-regulating pathways are involved in viral entry and exit. However, while the role of actin remodeling during entry is well understood, this is not the case during exit. We discuss remaining challenges regarding the actin-dependent mechanisms involved in HIV-1 entry and exit, and how they could be overcome.
Topics: Humans; Actins; HIV-1; Actin Cytoskeleton; Cell Line; Cell Membrane
PubMed: 36597754
DOI: 10.1111/boc.202200085 -
Current Biology : CB May 2021Septins are an integral component of the cytoskeleton, assembling into higher-order oligomers and filamentous polymers that associate with actin filaments, microtubules... (Review)
Review
Septins are an integral component of the cytoskeleton, assembling into higher-order oligomers and filamentous polymers that associate with actin filaments, microtubules and membranes. Here, we review septin interactions with actin and microtubules, and septin-mediated regulation of the organization and dynamics of these cytoskeletal networks, which is critical for cellular morphogenesis. We discuss how actomyosin-associated septins function in cytokinesis, cell migration and host defense against pathogens. We highlight newly emerged roles of septins at the interface of microtubules and membranes with molecular motors, which point to a 'septin code' for the regulation of membrane traffic. Additionally, we revisit the functions of microtubule-associated septins in mitosis and meiosis. In sum, septins comprise a unique module of cytoskeletal regulators that are spatially and functionally specialized and have properties of bona fide actin-binding and microtubule-associated proteins. With many questions still outstanding, the study of septins will continue to provide new insights into fundamental problems of cytoskeletal organization and function.
Topics: Actin Cytoskeleton; Actins; Animals; Humans; Microtubules; Septins
PubMed: 34033796
DOI: 10.1016/j.cub.2021.03.064 -
ELife Feb 2023Actin isoforms organize into distinct networks that are essential for the normal function of eukaryotic cells. Despite a high level of sequence and structure...
Actin isoforms organize into distinct networks that are essential for the normal function of eukaryotic cells. Despite a high level of sequence and structure conservation, subtle differences in their design principles determine the interaction with myosin motors and actin-binding proteins. Therefore, identifying how the structure of actin isoforms relates to function is important for our understanding of normal cytoskeletal physiology. Here, we report the high-resolution structures of filamentous skeletal muscle α-actin (3.37 Å), cardiac muscle α-actin (3.07 Å), ß-actin (2.99 Å), and γ-actin (3.38 Å) in the Mg·ADP state with their native post-translational modifications. The structures revealed isoform-specific conformations of the N-terminus that shift closer to the filament surface upon myosin binding, thereby establishing isoform-specific interfaces. Collectively, the structures of single-isotype, post-translationally modified bare skeletal muscle α-actin, cardiac muscle α-actin, ß-actin, and γ-actin reveal general principles, similarities, and differences between isoforms. They complement the repertoire of known actin structures and allow for a comprehensive understanding of in vitro and in vivo functions of actin isoforms.
Topics: Actins; Protein Isoforms; Myosins; Muscle, Skeletal; Actin Cytoskeleton
PubMed: 36790143
DOI: 10.7554/eLife.82015 -
The Journal of Medical Investigation :... 2017The adherens junction (AJ) is a cadherin-based and actin filament associated cell-to-cell junction. AJs can contribute to tissue morphogenesis and homeostasis and their... (Review)
Review
The adherens junction (AJ) is a cadherin-based and actin filament associated cell-to-cell junction. AJs can contribute to tissue morphogenesis and homeostasis and their association with actin filaments is crucial for the functions. There are three types of AJs in terms of the mode of actin filament/AJ association. Among many actin-binding proteins associated with AJs, α-catenin is one of the most important actin filament/AJ linkers that functions in all types of AJs. Although α-catenin in cadherin-catenin complex appears to bind to actin filaments within cells, it fails to bind to actin filaments in vitro mysteriously. Recent report revealed that α-catenin in the complex can bind to actin filaments in vitro when forces are applied to the filament. In addition to force-sensitive vinculin binding, α-catenin has another force-sensitive property of actin filament-binding. Elucidation of its significance and the molecular mechanism is indispensable for understanding AJ formation and maintenance during tissue morphogenesis, function and repair. J. Med. Invest. 64: 14-19, February, 2017.
Topics: Actin Cytoskeleton; Actins; Adherens Junctions; Animals; Humans; Protein Binding; Protein Interaction Domains and Motifs; alpha Catenin
PubMed: 28373611
DOI: 10.2152/jmi.64.14 -
Anatomical Record (Hoboken, N.J. : 2007) Dec 2018Actin is one of the most abundant intracellular proteins, essential in every eukaryotic cell type. Actin plays key roles in tissue morphogenesis, cell adhesion, muscle... (Review)
Review
Actin is one of the most abundant intracellular proteins, essential in every eukaryotic cell type. Actin plays key roles in tissue morphogenesis, cell adhesion, muscle contraction, and developmental reprogramming. Most actin studies have focused on its regulation at the protein level, either directly or through differential interactions with over a hundred intracellular binding partners. However, numerous studies emerging in recent years demonstrate specific types of nucleotide-level regulation that strongly affect non-muscle actins during cell migration and adhesion and are potentially applicable to other members of the actin family. This regulation involves zipcode-mediated actin mRNA targeting to the cell periphery, proposed to mediate local synthesis of actin at the cell leading edge, as well as the recently discovered N-terminal arginylation that specifically targets non-muscle β-actin via a nucleotide-dependent mechanism. Moreover, a study published this year suggests that actin's essential roles at the organismal level may be entirely nucleotide-dependent. This review summarizes the emerging data on actin's nucleotide-level regulation. Anat Rec, 301:1991-1998, 2018. © 2018 Wiley Periodicals, Inc.
Topics: Actin Cytoskeleton; Actins; Amino Acid Sequence; Animals; Humans; Protein Biosynthesis; Protein Processing, Post-Translational; RNA Interference
PubMed: 30312009
DOI: 10.1002/ar.23958 -
Blood May 2022
Topics: Actin Cytoskeleton; Actins; Extracellular Traps; Neutrophils
PubMed: 35616987
DOI: 10.1182/blood.2022015562 -
Journal of Cell Science Aug 2018In cells, actin filaments continuously assemble and disassemble while maintaining an apparently constant network structure. This suggests a perfect balance between... (Review)
Review
In cells, actin filaments continuously assemble and disassemble while maintaining an apparently constant network structure. This suggests a perfect balance between dynamic processes. Such behavior, operating far out of equilibrium by the hydrolysis of ATP, is called a dynamic steady state. This dynamic steady state confers a high degree of plasticity to cytoskeleton networks that allows them to adapt and optimize their architecture in response to external changes on short time-scales, thus permitting cells to adjust to their environment. In this Review, we summarize what is known about the cellular actin steady state, and what gaps remain in our understanding of this fundamental dynamic process that balances the different forms of actin organization in a cell. We focus on the minimal steps to achieve a steady state, discuss the potential feedback mechanisms at play to balance this steady state and conclude with an outlook on what is needed to fully understand its molecular nature.
Topics: Actin Cytoskeleton; Actins; Adenosine Triphosphate; Animals; Cytoskeleton; Ecosystem; Humans; Microtubules
PubMed: 30104258
DOI: 10.1242/jcs.219832