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Nature Reviews. Molecular Cell Biology Nov 2013Fuelled by ATP hydrolysis, dyneins generate force and movement on microtubules in a wealth of biological processes, including ciliary beating, cell division and... (Review)
Review
Fuelled by ATP hydrolysis, dyneins generate force and movement on microtubules in a wealth of biological processes, including ciliary beating, cell division and intracellular transport. The large mass and complexity of dynein motors have made elucidating their mechanisms a sizable task. Yet, through a combination of approaches, including X-ray crystallography, cryo-electron microscopy, single-molecule assays and biochemical experiments, important progress has been made towards understanding how these giant motor proteins work. From these studies, a model for the mechanochemical cycle of dynein is emerging, in which nucleotide-driven flexing motions within the AAA+ ring of dynein alter the affinity of its microtubule-binding stalk and reshape its mechanical element to generate movement.
Topics: Animals; Dyneins; Humans; Models, Biological
PubMed: 24064538
DOI: 10.1038/nrm3667 -
Experimental & Molecular Medicine Apr 2024Intracellular retrograde transport in eukaryotic cells relies exclusively on the molecular motor cytoplasmic dynein 1. Unlike its counterpart, kinesin, dynein has a... (Review)
Review
Intracellular retrograde transport in eukaryotic cells relies exclusively on the molecular motor cytoplasmic dynein 1. Unlike its counterpart, kinesin, dynein has a single isoform, which raises questions about its cargo specificity and regulatory mechanisms. The precision of dynein-mediated cargo transport is governed by a multitude of factors, including temperature, phosphorylation, the microtubule track, and interactions with a family of activating adaptor proteins. Activating adaptors are of particular importance because they not only activate the unidirectional motility of the motor but also connect a diverse array of cargoes with the dynein motor. Therefore, it is unsurprising that dysregulation of the dynein-activating adaptor transport machinery can lead to diseases such as spinal muscular atrophy, lower extremity, and dominant. Here, we discuss dynein motor motility within cells and in in vitro, and we present several methodologies employed to track the motion of the motor. We highlight several newly identified activating adaptors and their roles in regulating dynein. Finally, we explore the potential therapeutic applications of manipulating dynein transport to address diseases linked to dynein malfunction.
Topics: Humans; Cytoplasmic Dyneins; Animals; Biological Transport; Microtubules; Dyneins
PubMed: 38556551
DOI: 10.1038/s12276-024-01200-7 -
The Journal of Cell Biology Nov 2005A variety of names has been used in the literature for the subunits of cytoplasmic dynein complexes. Thus, there is a strong need for a more definitive consensus...
A variety of names has been used in the literature for the subunits of cytoplasmic dynein complexes. Thus, there is a strong need for a more definitive consensus statement on nomenclature. This is especially important for mammalian cytoplasmic dyneins, many subunits of which are encoded by multiple genes. We propose names for the mammalian cytoplasmic dynein subunit genes and proteins that reflect the phylogenetic relationships of the genes and the published studies clarifying the functions of the polypeptides. This nomenclature recognizes the two distinct cytoplasmic dynein complexes and has the flexibility to accommodate the discovery of new subunits and isoforms.
Topics: Animals; Cytoplasm; Dyneins; Humans; Terminology as Topic
PubMed: 16260502
DOI: 10.1083/jcb.200508078 -
ELife Jan 2022The lissencephaly 1 gene, , is mutated in patients with the neurodevelopmental disease lissencephaly. The Lis1 protein is conserved from fungi to mammals and is a key...
The lissencephaly 1 gene, , is mutated in patients with the neurodevelopmental disease lissencephaly. The Lis1 protein is conserved from fungi to mammals and is a key regulator of cytoplasmic dynein-1, the major minus-end-directed microtubule motor in many eukaryotes. Lis1 is the only dynein regulator known to bind directly to dynein's motor domain, and by doing so alters dynein's mechanochemistry. Lis1 is required for the formation of fully active dynein complexes, which also contain essential cofactors: dynactin and an activating adaptor. Here, we report the first high-resolution structure of the yeast dynein-Lis1 complex. Our 3.1 Å structure reveals, in molecular detail, the major contacts between dynein and Lis1 and between Lis1's ß-propellers. Structure-guided mutations in Lis1 and dynein show that these contacts are required for Lis1's ability to form fully active human dynein complexes and to regulate yeast dynein's mechanochemistry and in vivo function.
Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Cytoplasmic Dyneins; Dyneins; Gene Expression Regulation; Microtubule-Associated Proteins; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 34994688
DOI: 10.7554/eLife.71229 -
Cells Feb 2024Dynein, an ancient microtubule-based motor protein, performs diverse cellular functions in nearly all eukaryotic cells, with the exception of land plants. It has evolved... (Review)
Review
Dynein, an ancient microtubule-based motor protein, performs diverse cellular functions in nearly all eukaryotic cells, with the exception of land plants. It has evolved into three subfamilies-cytoplasmic dynein-1, cytoplasmic dynein-2, and axonemal dyneins-each differentiated by their cellular functions. These megadalton complexes consist of multiple subunits, with the heavy chain being the largest subunit that generates motion and force along microtubules by converting the chemical energy of ATP hydrolysis into mechanical work. Beyond this catalytic core, the functionality of dynein is significantly enhanced by numerous non-catalytic subunits. These subunits are integral to the complex, contributing to its stability, regulating its enzymatic activities, targeting it to specific cellular locations, and mediating its interactions with other cofactors. The diversity of non-catalytic subunits expands dynein's cellular roles, enabling it to perform critical tasks despite the conservation of its heavy chains. In this review, we discuss recent findings and insights regarding these non-catalytic subunits.
Topics: Cytoplasmic Dyneins; Catalytic Domain; Dyneins
PubMed: 38391943
DOI: 10.3390/cells13040330 -
Biology of the Cell Jan 2013Active transport along the microtubule lattice is a complex process that involves both the Kinesin and Dynein superfamily of motors. Transportation requires... (Review)
Review
Active transport along the microtubule lattice is a complex process that involves both the Kinesin and Dynein superfamily of motors. Transportation requires sophisticated regulation much of which occurs through the motor's tail domain. However, a significant portion of this regulation also occurs through structural changes that arise in the motor and the microtubule upon binding. The most obvious structural change being the manifestation of asymmetry. To a first approximation in solution, kinesin dimers exhibit twofold symmetry, and microtubules exhibit helical symmetry. The higher symmetries of both the kinesin dimers and microtubule lattice are lost on formation of the kinesin-microtubule complex. Loss of symmetry has functional consequences such as an asymmetric hand-over-hand mechanism in plus-end-directed kinesins, asymmetric microtubule binding in the Kinesin-14 family, spatially biased stepping in dynein and cooperative binding of additional motors to the microtubule. This review focusses on how the consequences of asymmetry affect regulation of motor heads within a dimer, dimers within an ensemble of motors, and suggests how these asymmetries may affect regulation of active transport within the cell.
Topics: Dyneins; Humans; Kinesins; Microtubules; Protein Binding; Protein Multimerization; Tubulin
PubMed: 23066835
DOI: 10.1111/boc.201200044 -
The Journal of Biological Chemistry Sep 2019Dyneins are ATP-fueled macromolecular machines that power all minus-end microtubule-based transport processes of molecular cargo within eukaryotic cells and play... (Review)
Review
Dyneins are ATP-fueled macromolecular machines that power all minus-end microtubule-based transport processes of molecular cargo within eukaryotic cells and play essential roles in a wide variety of cellular functions. These complex and fascinating motors have been the target of countless structural and biophysical studies. These investigations have elucidated the mechanism of ATP-driven force production and have helped unravel the conformational rearrangements associated with the dynein mechanochemical cycle. However, despite decades of research, it remains unknown how these molecular motions are harnessed to power massive cellular reorganization and what are the regulatory mechanisms that drive these processes. Recent advancements in electron tomography imaging have enabled researchers to visualize dynein motors in their transport environment with unprecedented detail and have led to exciting discoveries regarding dynein motor function and regulation. In this review, we will highlight how these recent structural studies have fundamentally propelled our understanding of the dynein motor and have revealed some unexpected, unifying mechanisms of regulation.
Topics: Biological Transport; Dyneins; Electron Microscope Tomography; Humans
PubMed: 31285262
DOI: 10.1074/jbc.REV119.003095 -
Journal of Cell Science Aug 2021Axonemal dyneins power the beating of motile cilia and flagella. These massive multimeric motor complexes are assembled in the cytoplasm, and subsequently trafficked to...
Axonemal dyneins power the beating of motile cilia and flagella. These massive multimeric motor complexes are assembled in the cytoplasm, and subsequently trafficked to cilia and incorporated into the axonemal superstructure. Numerous cytoplasmic factors are required for the dynein assembly process, and, in mammals, defects lead to primary ciliary dyskinesia, which results in infertility, bronchial problems and failure to set up the left-right body axis correctly. Liquid-liquid phase separation (LLPS) has been proposed to underlie the formation of numerous membrane-less intracellular assemblies or condensates. In multiciliated cells, cytoplasmic assembly of axonemal dyneins also occurs in condensates that exhibit liquid-like properties, including fusion, fission and rapid exchange of components both within condensates and with bulk cytoplasm. However, a recent extensive meta-analysis suggests that the general methods used to define LLPS systems in vivo may not readily distinguish LLPS from other mechanisms. Here, I consider the time and length scales of axonemal dynein heavy chain synthesis, and the possibility that during translation of dynein heavy chain mRNAs, polysomes are crosslinked via partially assembled proteins. I propose that axonemal dynein factory formation in the cytoplasm may be a direct consequence of the sheer scale and complexity of the assembly process itself.
Topics: Animals; Axonemal Dyneins; Axoneme; Cilia; Cytoplasm; Dyneins; Flagella
PubMed: 34342348
DOI: 10.1242/jcs.258626 -
The Journal of Cell Biology Jul 2013Dynein is a microtubule-based molecular motor that is involved in various biological functions, such as axonal transport, mitosis, and cilia/flagella movement. Although... (Review)
Review
Dynein is a microtubule-based molecular motor that is involved in various biological functions, such as axonal transport, mitosis, and cilia/flagella movement. Although dynein was discovered 50 years ago, the progress of dynein research has been slow due to its large size and flexible structure. Recent progress in understanding the force-generating mechanism of dynein using x-ray crystallography, cryo-electron microscopy, and single molecule studies has provided key insight into the structure and mechanism of action of this complex motor protein.
Topics: Adenosine Triphosphate; Animals; Axoneme; Binding Sites; Biomechanical Phenomena; Chlamydomonas reinhardtii; Cilia; Dyneins; Flagella; Models, Molecular; Multiprotein Complexes; Protein Structure, Tertiary; Structure-Activity Relationship
PubMed: 23836927
DOI: 10.1083/jcb.201304099 -
Viruses Apr 2020Following entry into the host cell, retroviruses generate a dsDNA copy of their genomes via reverse transcription, and this viral DNA is subsequently integrated into the... (Review)
Review
Following entry into the host cell, retroviruses generate a dsDNA copy of their genomes via reverse transcription, and this viral DNA is subsequently integrated into the chromosomal DNA of the host cell. Before integration can occur, however, retroviral DNA must be transported to the nucleus as part of a 'preintegration complex' (PIC). Transporting the PIC through the crowded environment of the cytoplasm is challenging, and retroviruses have evolved different mechanisms to accomplish this feat. Within a eukaryotic cell, microtubules act as the roads, while the microtubule-associated proteins dynein and kinesin are the vehicles that viruses exploit to achieve retrograde and anterograde trafficking. This review will examine the various mechanisms retroviruses have evolved in order to achieve retrograde trafficking, confirming that each retrovirus has its own strategy to functionally subvert microtubule associated proteins.
Topics: Biological Transport; Dyneins; Host-Pathogen Interactions; Humans; Microtubule-Associated Proteins; Microtubules; Molecular Motor Proteins; Retroviridae; Virus Replication
PubMed: 32344581
DOI: 10.3390/v12040483