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Functions and Mechanics of Dynein Motor Proteins

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Functions and Mechanics of Dynein Motor Proteins REVIEWS Functions and mechanics of dynein motor proteins Anthony J. Roberts1,2, Takahide Kon3,4, Peter J. Knight1, Kazuo Sutoh5 and Stan A. Burgess1 Abstract | 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. To move, divide and spatially organize their teeming cytoskeletal polymers — these motors share a G protein- 1Astbury Centre for Structural interiors, eukaryotic cells use ATP-fuelled motor pro- related fold and similarities in their core mechanisms9. Molecular Biology, School of teins to generate forces and transport cargoes along Dynein is currently at the frontier of cell motility Molecular and Cellular Biology, Faculty of Biological cytoskeletal tracks. The numerous proteins, organelles research at the molecular level, as its mechanism of move- Sciences, University of Leeds, and mRNAs that undergo directed transport by motor ment is much less well understood than that of kinesin Leeds LS2 9JT, UK. proteins touch on a wide range of cellular and devel- and myosin. Dubbed the ‘big wheel’ of motor proteins10, 2Department of Cell Biology, opmental processes. Underscoring the importance of dynein belongs to the AAA+ superfamily (ATPases asso- Harvard Medical School, cytoskeletal motors in biology, it is now clear that seri- ciated with diverse activities)11. Conventional AAA+ 240 Longwood Avenue, Boston, Massachusetts ous human and animal diseases arise from motor protein ATPases function as hexameric rings that unfold proteins, 1,2 02115, USA. dysfunction . dismantle DNA and RNA duplexes and pry apart macro- 3Department of Frontier Dynein is one of the three families of cytoskeletal molecular complexes and aggregates11. Like conventional Bioscience, Faculty of motor protein. Originally identified 50 years ago as AAA+ ATPases, dynein has a ring of six AAA+ modules Bioscience and Applied 3 Chemistry, Hosei University, an ATPase in Tetrahymena pyriformis cilia , dynein at its core but, unusually, these are linked together into one 3‑7‑2 Kajino-cho, Koganei, was named by Gibbons and Rowe after the unit of large polypeptide, along with several unique appendages Tokyo 184-8584, Japan. force, the dyne4. A cytoplasmic form of dynein was that enable motor function. The large size and complexity 4Japan Science and subsequently isolated from brain tissue5 and shown to of dynein have made elucidating its mechanism a formi- Technology Agency, PRESTO, drive intra­cellular transport towards the minus ends of dable task. However, recent studies have risen to this chal- 4‑1‑8 Honcho, Kawaguchi, 6,7 Saitama 332-0012, Japan. micro­tubules , which typically lie in the microtubule- lenge using various approaches. For example, in the past 5Faculty of Science and organizing centre near the nucleus in non-dividing cells 2 years, long sought-after crystal structures of the motor Engineering, Waseda (FIG. 1). The discovery of dynein thus complemented the domain of dynein have been solved, and single-molecule University, Okubo 3‑4‑1, finding of kinesins8; microtubule-based motors that studies, live-cell imaging and electron microscopy have Shinjuku‑ku, Tokyo 169-8555, Japan. typically move towards the plus ends of microtubules provided key insights into the dynamics of dynein. Correspondence to and hence the cell periphery. In this Review, we focus on advances in two main A.J.R and S.A.B Given that dyneins and kinesins both move along areas: first, the cellular functions of dyneins, and second, e‑mails: Anthony_Roberts@ microtubules, one might have expected their mecha- the molecular mechanism of the dynein motor domain. hms.harvard.edu; nisms of motility to have more in common with one Exciting progress has also been made in understand- [email protected] doi:10.1038/nrm3667 another than with the actin-based motor, myosin. It was ing how dyneins are regulated and recruited to specific Published online therefore a surprise when crystal structures of myosin cargoes in the cell, and the reader is referred to recent 25 September 2013 and kinesin revealed that — despite moving on different reviews on these topics12–19. NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 14 | NOVEMBER 2013 | 713 © 2013 Macmillan Publishers Limited. All rights reserved REVIEWS a Chromosome Pulling force on Kinetochore microtubule network from cell cortex + + Microtubule Focusing microtubule + minus ends at spindle poles + + + + Microtubule + Nuclear positioning, + + + + migration and + breakdown + + Golgi + + Pulling force + + Transport of diverse cargo on spindle towards microtubule minus end Nucleus + + + Kinetochore–microtubule interactions and spindle Perinuclear + checkpoint inactivation positioning of Golgi + b Retrograde IFT Microtubule Axoneme + Ciliary beating Figure 1 | Sites of dynein action in the cell. a | Example functions of cytoplasmic dynein (green) are shown in an interphase cell (left) and a dividing cell (right). The polarity of microtubules is indicatedNature by Reviews plus signs. | Molecular The arrow Cell depicts Biology the direction of dynein movement towards the microtubule minus end. Note that in some cell types and regions, such as the dendritic arbors of neurons, the microtubule network can have mixed polarity. b | Dynein functions in cilia. Intraflagellar transport (IFT) dynein (pink) performs retrograde IFT, whereas axonemal dyneins (cyan) power the beating of motile cilia. Overview of the dynein family In this Review, we refer to cyto­plasmic dynein 1 as ‘cyto­ Dyneins operate as protein complexes built around plasmic dynein’ and cytoplasmic dynein 2 as ‘intra­ force-generating subunits called heavy chains, so flagellar transport (IFT) dynein’ for distinction. The termed because of their large molecular mass (typi- remaining seven dynein classes are built into the axoneme, cally ~500 kDa) (FIG. 2). Each heavy chain contains a where they power ciliary beating (BOX 1). Some axonemal motor domain that belongs to the AAA+ superfamily11 dynein classes have multiple representatives per genome, G protein-related fold attached to a divergent amino‑terminal tail domain so the total number of distinct heavy chain genes in A characteristic arrangement (FIG. 2a). The tail specifies distinct oligomerization prop- organisms that build a motile axoneme typically exceeds of secondary structure erties and serves as a platform for the binding of several nine. For example, there are 16 dynein heavy chain genes elements and loops (such as types of associated subunit (FIG. 2b), which in turn medi- in the human genome22. switch I and switch II) shared by G proteins, myosins and ate interactions with cargo either via direct binding or kinesins, which indicates that through the recruitment of adaptor proteins. Functions of cytoplasmic dynein these proteins originated from Phylogenetically, there are nine major classes of Cytoplasmic dynein performs a great variety of cellular a common ancestor. dynein heavy chain20. The cytoplasmic dynein 1 heavy functions. The breadth of these activities seems to be Axoneme chain (encoded by DYNC1H1 in humans) is used for greatest in metazoan cells (described below), but cyto- The microtubule-based core nearly all of the minus end-directed transport in the cyto- plasnic dynein is also used to varying extents in fungi, of eukaryotic cilia and flagella. plasm of most eukaryotic cells (FIG. 1a). However, archae- alveolata, stramenopila and amoebozoa20. For example, The terms cilia and flagella are plastidans, which lack dyneins and possess an expanded in the yeast Saccharomyces cerevisiae, the sole known role often used interchangeably, repertoire of minus end-directed kinesins21, are an excep- of cytoplasmic dynein is positioning the nucleus during as both describe cellular 23 24 appendages with an axoneme tion. Cytoplasmic dynein 2 (encoded by DYNC2H1 in cell division , whereas in filamentous fungi and the 25 at their core. In this Review, we humans) has a specialized role in transporting mate- slime mould Dictyostelium discoideum it is also used use cilia for consistency. rial along motile and sensory cilia and flagella (FIG. 1b). for vesicle transport. 714 | NOVEMBER 2013 | VOLUME 14 www.nature.com/reviews/molcellbio © 2013 Macmillan Publishers Limited. All rights reserved REVIEWS a Motor domain c Linker C Tail Linker 1 2 3 4 Stalk 5 Strut 6 C 1 Main ATPase site Direction of 6 movement 2 Nucleotide Binding and/or AAA+ module binding hydrolysis 5 Large and small 3 subdomains Strut 4 b Cargo and/or adaptor binding Tail Intermediate chain Light chains Stalk N N Microtubule-binding TCTEX domain Strut (or buttress) LC8 α β Tubulin Linker Neck Roadblock Stalk Microtubule-binding Light-intermediate 8 nm domain chain Figure 2 | Overview of dynein composition. a | Linear representation of domains within the dynein heavy chain. Nature Reviews | Molecular Cell Biology The amino‑terminal tail domain
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