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Journal of Experimental & Clinical... May 2023Disulfidptosis, a new form of cell death triggered by disulfide stress, is characterized by the collapse of cytoskeleton proteins and F-actin due to the intracellular...
Disulfidptosis, a new form of cell death triggered by disulfide stress, is characterized by the collapse of cytoskeleton proteins and F-actin due to the intracellular accumulation of disulfides. This discovery will eventually aid in the development of therapeutic strategies against cancer.
Topics: Humans; Apoptosis; Actins; Actin Cytoskeleton; Cell Death; Cytoskeletal Proteins
PubMed: 37259067
DOI: 10.1186/s13046-023-02712-2 -
Current Biology : CB May 2021Actin is one of the most abundant proteins in eukaryotes. Discovered in muscle and described as far back as 1887, actin was first purified in 1942. It plays myriad roles...
Actin is one of the most abundant proteins in eukaryotes. Discovered in muscle and described as far back as 1887, actin was first purified in 1942. It plays myriad roles in essentially every eukaryotic cell. Actin is central to development, muscle contraction, and cell motility, and it also functions in the nucleus, to name a spectrum of examples. The flexibility of actin function stems from two factors: firstly, it is dynamic, transitioning between monomer and filament, and, secondly, there are hundreds of actin-binding proteins that build and organize specific actin-based structures. Of prime importance are actin nucleators - proteins that stimulate de novo formation of actin filaments. There are three known classes of actin nucleators: the Arp2/3 complex, formins, and tandem WASP homology 2 (WH2) nucleators. Each class nucleates by a distinct mechanism that contributes to the organization of the larger structure being built. Evidence shows that the Arp2/3 complex produces branched actin filaments, remaining bound at the branch point, while formins create linear actin filaments, remaining bound at the growing end. Here, we focus on the formin family of actin nucleators.
Topics: Actin Cytoskeleton; Actin-Related Protein 2-3 Complex; Actins; Formins; Microfilament Proteins
PubMed: 34033783
DOI: 10.1016/j.cub.2021.02.047 -
Nature Nov 2022The dynamic turnover of actin filaments (F-actin) controls cellular motility in eukaryotes and is coupled to changes in the F-actin nucleotide state. It remains unclear...
The dynamic turnover of actin filaments (F-actin) controls cellular motility in eukaryotes and is coupled to changes in the F-actin nucleotide state. It remains unclear how F-actin hydrolyses ATP and subsequently undergoes subtle conformational rearrangements that ultimately lead to filament depolymerization by actin-binding proteins. Here we present cryo-electron microscopy structures of F-actin in all nucleotide states, polymerized in the presence of Mg or Ca at approximately 2.2 Å resolution. The structures show that actin polymerization induces the relocation of water molecules in the nucleotide-binding pocket, activating one of them for the nucleophilic attack of ATP. Unexpectedly, the back door for the subsequent release of inorganic phosphate (P) is closed in all structures, indicating that P release occurs transiently. The small changes in the nucleotide-binding pocket after ATP hydrolysis and P release are sensed by a key amino acid, amplified and transmitted to the filament periphery. Furthermore, differences in the positions of water molecules in the nucleotide-binding pocket explain why Ca-actin shows slower polymerization rates than Mg-actin. Our work elucidates the solvent-driven rearrangements that govern actin filament assembly and aging and lays the foundation for the rational design of drugs and small molecules for imaging and therapeutic applications.
Topics: Actin Cytoskeleton; Actins; Adenosine Triphosphate; Cryoelectron Microscopy; Hydrolysis; Nucleotides; Water; Aging; Magnesium; Calcium; Amino Acids; Phosphates
PubMed: 36289337
DOI: 10.1038/s41586-022-05241-8 -
Sub-cellular Biochemistry 2022Formation of cross-bridges between actin and myosin occurs ubiquitously in eukaryotic cells and mediates muscle contraction, intracellular cargo transport, and...
Formation of cross-bridges between actin and myosin occurs ubiquitously in eukaryotic cells and mediates muscle contraction, intracellular cargo transport, and cytoskeletal remodeling. Myosin motors repeatedly bind to and dissociate from actin filaments in a cycle that transduces the chemical energy from ATP hydrolysis into mechanical force generation. While the general layout of surface elements within the actin-binding interface is conserved among myosin classes, sequence divergence within these motifs alters the specific contacts involved in the actomyosin interaction as well as the kinetics of mechanochemical cycle phases. Additionally, diverse lever arm structures influence the motility and force production of myosin molecules during their actin interactions. The structural differences generated by myosin's molecular evolution have fine-tuned the kinetics of its isoforms and adapted them for their individual cellular roles. In this chapter, we will characterize the structural and biochemical basis of the actin-myosin interaction and explain its relationship with myosin's cellular roles, with emphasis on the structural variation among myosin isoforms that enables their functional specialization. We will also discuss the impact of accessory proteins, such as the troponin-tropomyosin complex and myosin-binding protein C, on the formation and regulation of actomyosin cross-bridges.
Topics: Actin Cytoskeleton; Actins; Actomyosin; Adenosine Triphosphate; Myosins; Protein Isoforms
PubMed: 36151385
DOI: 10.1007/978-3-031-00793-4_14 -
Current Biology : CB May 2021Robert Insall introduces the cytoskeleton special issue and summarises some recent changes in our view of actin function and regulation.
Robert Insall introduces the cytoskeleton special issue and summarises some recent changes in our view of actin function and regulation.
Topics: Actin Cytoskeleton; Actins; Cytoskeleton; Microtubules
PubMed: 34033777
DOI: 10.1016/j.cub.2021.04.013 -
Current Biology : CB May 2021Cell morphology, architecture and dynamics primarily rely on intracellular cytoskeletal networks, which in metazoans are mainly composed of actin microfilaments,...
Cell morphology, architecture and dynamics primarily rely on intracellular cytoskeletal networks, which in metazoans are mainly composed of actin microfilaments, microtubules and intermediate filaments (IFs). The diameter size of 10 nm - intermediate between the diameters of actin microfilaments and microtubules - initially gave IFs their name. However, the structure, dynamics, mechanical properties and functions of IFs are not intermediate but set them apart from actin and microtubules. Because of their nucleotide-independent assembly, the lack of intrinsic polarity, their relative stability and their complex composition, IFs had long been overlooked by cell biologists. Now, the numerous human diseases identified to be associated with IF gene mutations and the accumulating evidence of IF functions in cell and tissue integrity explain the growing attention that is being given to the structural characteristics, dynamics and functions of these filaments. In this Primer, we highlight the growing evidence that has revealed a role for IFs as a key element of the cytoskeleton, providing versatile, tunable, cell-type-specific filamentous networks with unique cytoplasmic and nuclear functions.
Topics: Actin Cytoskeleton; Actins; Cytoskeleton; Humans; Intermediate Filaments; Microtubules
PubMed: 34033784
DOI: 10.1016/j.cub.2021.04.011 -
Nature Mar 2021Symmetric cell division requires the even partitioning of genetic information and cytoplasmic contents between daughter cells. Whereas the mechanisms coordinating the...
Symmetric cell division requires the even partitioning of genetic information and cytoplasmic contents between daughter cells. Whereas the mechanisms coordinating the segregation of the genome are well known, the processes that ensure organelle segregation between daughter cells remain less well understood. Here we identify multiple actin assemblies with distinct but complementary roles in mitochondrial organization and inheritance in mitosis. First, we find a dense meshwork of subcortical actin cables assembled throughout the mitotic cytoplasm. This network scaffolds the endoplasmic reticulum and organizes three-dimensional mitochondrial positioning to ensure the equal segregation of mitochondrial mass at cytokinesis. Second, we identify a dynamic wave of actin filaments reversibly assembling on the surface of mitochondria during mitosis. Mitochondria sampled by this wave are enveloped within actin clouds that can spontaneously break symmetry to form elongated comet tails. Mitochondrial comet tails promote randomly directed bursts of movement that shuffle mitochondrial position within the mother cell to randomize inheritance of healthy and damaged mitochondria between daughter cells. Thus, parallel mechanisms mediated by the actin cytoskeleton ensure both equal and random inheritance of mitochondria in symmetrically dividing cells.
Topics: Actin Cytoskeleton; Actins; Animals; Cell Division; Cell Line; Cytokinesis; Endoplasmic Reticulum; Hippocampus; Humans; Mitochondria; Mitosis; Neurons; Rats
PubMed: 33658713
DOI: 10.1038/s41586-021-03309-5 -
Current Biology : CB May 2021Arit Ghosh and Velia Fowler introduce the structural features and functions of tropomodulins - actin-binding proteins that cap the slow-growing (pointed) ends of actin...
Arit Ghosh and Velia Fowler introduce the structural features and functions of tropomodulins - actin-binding proteins that cap the slow-growing (pointed) ends of actin filaments.
Topics: Actin Cytoskeleton; Actins; Microfilament Proteins; Tropomodulin
PubMed: 34033779
DOI: 10.1016/j.cub.2021.01.055 -
Cell Apr 2023The spectrin-based membrane skeleton is a ubiquitous membrane-associated two-dimensional cytoskeleton underneath the lipid membrane of metazoan cells. Mutations of...
The spectrin-based membrane skeleton is a ubiquitous membrane-associated two-dimensional cytoskeleton underneath the lipid membrane of metazoan cells. Mutations of skeleton proteins impair the mechanical strength and functions of the membrane, leading to several different types of human diseases. Here, we report the cryo-EM structures of the native spectrin-actin junctional complex (from porcine erythrocytes), which is a specialized short F-actin acting as the central organizational unit of the membrane skeleton. While an α-/β-adducin hetero-tetramer binds to the barbed end of F-actin as a flexible cap, tropomodulin and SH3BGRL2 together create an absolute cap at the pointed end. The junctional complex is strengthened by ring-like structures of dematin in the middle actin layers and by patterned periodic interactions with tropomyosin over its entire length. This work serves as a structural framework for understanding the assembly and dynamics of membrane skeleton and offers insights into mechanisms of various ubiquitous F-actin-binding factors in other F-actin systems.
Topics: Animals; Humans; Actin Cytoskeleton; Actins; Cytoskeleton; Erythrocytes; Spectrin; Swine
PubMed: 37044097
DOI: 10.1016/j.cell.2023.03.017 -
Biology Open Dec 2022Actin, one of the most abundant intracellular proteins in mammalian cells, is a critical regulator of cell shape and polarity, migration, cell division, and... (Review)
Review
Actin, one of the most abundant intracellular proteins in mammalian cells, is a critical regulator of cell shape and polarity, migration, cell division, and transcriptional response. Angiogenesis, or the formation of new blood vessels in the body is a well-coordinated multi-step process. Endothelial cells lining the blood vessels acquire several new properties such as front-rear polarity, invasiveness, rapid proliferation and motility during angiogenesis. This is achieved by changes in the regulation of the actin cytoskeleton. Actin remodelling underlies the switch between the quiescent and angiogenic state of the endothelium. Actin forms endothelium-specific structures that support uniquely endothelial functions. Actin regulators at endothelial cell-cell junctions maintain the integrity of the blood-tissue barrier while permitting trans-endothelial leukocyte migration. This review focuses on endothelial actin structures and less-recognised actin-mediated endothelial functions. Readers are referred to other recent reviews for the well-recognised roles of actin in endothelial motility, barrier functions and leukocyte transmigration. Actin generates forces that are transmitted to the extracellular matrix resulting in vascular matrix remodelling. In this review, we attempt to synthesize our current understanding of the roles of actin in vascular morphogenesis. We speculate on the vascular bed specific differences in endothelial actin regulation and its role in the vast heterogeneity in endothelial morphology and function across the various tissues of our body.
Topics: Animals; Actins; Endothelial Cells; Actin Cytoskeleton; Cell Movement; Morphogenesis; Mammals
PubMed: 36444960
DOI: 10.1242/bio.058899