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Axonemal Dynein Arms Downloaded from http://cshperspectives.cshlp.org/ on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press Axonemal Dynein Arms Stephen M. King Department of Molecular Biology and Biophysics, University of Connecticut Health Center, Farmington, Connecticut 06030-3305 Correspondence: [email protected] Axonemal dyneins form the inner and outer rows of arms associated with the doublet mi- crotubules of motile cilia. These enzymes convert the chemical energy released from aden- osine triphosphate (ATP) hydrolysis into mechanical work by causing the doublets to slide with respect to each other. Dyneins form two major groups based on the number of heavy- chain motors within each complex. In addition, these enzymes contain other components that are required for assembly of the complete particles and/or for the regulation of motor function in response to phosphorylations status, ligands such as Ca2þ, changes in cellular redox state and which also apparently monitor and respond to the mechanical state or cur- vature in which any given motor finds itself. It is this latter property, which is thought to result in waves of motor function propagating along the axoneme length. Here, I briefly describe our current understanding of axonemal dynein structure, assembly, and organization. otile cilia1 are organelles involved in the superstructure is complex, ultimately the motile Mtransport of fluids (such as mucus flow behavior is generated by two rows of dynein in the lungs) and in the directed movement of arms that are permanently attached to the A- individual cells (e.g., sperm). Reactivation of tubule of one microtubule doublet and tran- demembranated organelles has clearly shown siently interact in an adenosine triphosphate that all the components necessary to generate (ATP)-dependent manner with the B-tubule and propagate waveforms are built into the mi- of an adjacent doublet. This generates a sliding crotubular axoneme, which can thus be consid- force that is converted to bending by additional ered a solid-state (or hard-wired) motility sys- structures (including the nexin–dynein regula- tem requiring only an external energy source to tory complex) that link the doublets circumfer- function. Indeed, in vitro, these structures even entially. In this article, I briefly describe the ba- retain the ability to alter their waveform or beat sic composition of these dynein complexes and frequency in response to alterations in added how they are preassembled in cytoplasm and signaling factors. Although the path by which trafficked into the ciliary shaft. I also discuss signals are propagated through the axonemal how they are incorporated into the axoneme, their patterning within the superstructure, the mechanisms by which they are regulated to generate specific ciliary beat patterns, and the 1In some organisms, such as Chlamydomonas, this organelle is com- monly referred to as a flagellum. However, here I use the term cilium general consequences of their dysfunction in throughout for clarity. mammals. Editors: Wallace Marshall and Renata Basto Additional Perspectives on Cilia available at www.cshperspectives.org Copyright # 2016 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a028100 Cite this article as Cold Spring Harb Perspect Biol 2016;8:a028100 1 Downloaded from http://cshperspectives.cshlp.org/ on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press S.M. King As dyneins are highly complex macro- their discrete localization in the region of the molecular systems containing, in some cases, axoneme near the ciliary base supports the .20 different protein components, and as idea that they may be involved in bend initia- they have been studied over many years in nu- tion. Chlamydomonas mutants defective for merous different model systems, their nomen- actin are actually viable and the lack of this clature has become extraordinarily complex and protein leads to the failure of most of these highly confusing. Here, I use the nomenclature monomeric heavy-chain dyneins to assemble scheme used in Chlamydomonas; to translate (Kato-Minoura et al. 1997). However, it has this to orthologous components in other organ- been observed that two particular motors are isms, the reader is referred to Hom et al. (2011), still incorporated into the axonemal superstruc- which presents a comprehensive taxonomic ture as they are able to use an actin-related pro- guide to axonemal dynein nomenclature. tein that becomes up-regulated in the mutant strain (Kato-Minoura et al. 1998). The p28 light chain is also absolutely required for the assem- COMPOSITION OF DYNEIN ARMS bly of those dyneins with which it associates The dynein arms that powerciliary motility may (LeDizet and Piperno 1995). be classified into two distinct groups based on The second dynein class includes both the the number of heavy-chain motor units that outer arm (Fig. 1C) and an additional inner arm they contain. These motors are 4500 residues termed I1 or f (see Table 1). These motors are and consist of an amino-terminal region re- built in a manner related to that of canonical quired for assembly, followed by a motor unit cytoplasmic dynein and the dynein that powers consisting of a hexameric ring of nonidentical retrograde intraflagellar transport (IFT). In all AAAþ domains (Fig. 1A,B). The microtubule- of these complexes, two heavy-chain motors (or binding region is located at the tip of a coiled three in the case of outer arms in organisms coil that emanates from AAA4 and also interacts such as Chlamydomonas and Tetrahymena) as- with a second coiled-coil segment (termed the sociate together via their amino-terminal re- buttress) that derives from AAA5. Finally, there gions. Cytoplasmic and IFT dyneins are formed is a carboxy-terminal domain that associates from homodimers of heavy chains. However, across the plane of the AAA ring and may be for axonemal dyneins these multimotor en- involved in regulating motor activity. zymes contain nonidentical heavy chains en- The first dynein class consists of single mo- coded by different genes that show distinct tors that are associated with a molecule of actin motor and ATPase properties; indeed, the indi- and either a specific light chain (termed p28 vidual motor units within the same complex in Chlamydomonas; dyneins a, c, and d) or the are even regulated by different signaling inputs. Ca2þ-binding protein centrin (dyneins b, e, The heavy-chain amino-terminal segments and g); dynein d also has two additional com- also bind an additional subcomplex consisting ponents p38 and p44. These motors form a sub- of two WD-repeat intermediate chains and set of the inner dynein arms and are arrayed in light chains belonging to three conserved classes a complex manner both along the axonemal (namely, DYNLL1/2 or LC8, DYNLT1 or length and potentially even on distinct outer Tctex1, and DYNLRB1/2, roadblock, or LC7) doublets. In addition to this major group of (King and Patel-King 1995b; Harrison et al. monomeric dyneins, there are also several “mi- 1998; Bowman et al. 1999). This subcomplex nor” dyneins that are present in greatly reduced is absolutely required for motor integrity and quantity (Yagi et al. 2009). In Chlamydomonas, assembly and, for example, mutants defective one of these (termed DHC3) is estimated to be for the outer arm WD-repeat intermediate almost 100 kDa larger than other dyneins be- chains are completely unable to assemble these cause of a series of insertions within the AAAþ structures into the axoneme (Mitchell and Kang ring domain. Although little is known about the 1991; Wilkerson et al. 1995). The outer arms composition or role of these minor isoforms, from metazoans also contain an additional in- 2 Cite this article as Cold Spring Harb Perspect Biol 2016;8:a028100 Downloaded from A MT-binding http://cshperspectives.cshlp.org/ Cite this article as N DHC_N1 DHC_N2 AAA1 AAA2 AAA3 AAA4 AAA5 AAA6 C C Coiled coil B-tubule Tubulin Cold Spring Harb Perspect Biol MT-binding domain C B LC1 onSeptember28,2021-PublishedbyColdSpringHarborLaboratoryPress Buttress Coiled-coil stalk Linker Lis1 α β γ Carboxy-terminal domain 4 5 2016;8:a028100 6 LC5 LC3 3 AAA ring LC4 2 1 IC1 LC6 LC9 LC10 LC8 LC7a Amino-terminal tail LC2 LC6 LC9 LC10 LC8 LC7b IC2 DC2 DC3 DC1 Tubulin A-tubule Axonemal Dynein Arms Figure 1. Organization of axonemal dynein motors. (A) Linear map of a generic 4500-residue dynein heavy chain. The amino-terminal region contains two conserved segments found in nearly all these motors: DHC_N1 is involved in heavy- chain assembly, whereas DHC_N2 represents the linker that traverses the plane of the AAA ring and is key to the power stroke mechanism. This is followed by the hexameric AAA ring and carboxy-terminal domain. (From King 2012a; modified, with permission, from the author.) (B) Model of a single dynein heavy chain showing how the various domains are arranged. (From King 2010; modified, with permission, from the author.) (C) Diagram showing the interactions of the core components that comprise the Chlamydomonas outer dynein arm. The heavy chains interact with a series of proteins that provide regulatory inputs (LCs1, 3, 4, and 5, and Lis1). They also bind to the intermediate-chain/light-chain complex, 3 which in turn associates with the trimeric docking complex. The general properties of all these components are indicated in Table 1. MT, Microtubule. (From King 2012b; modified, with permission, from the author.) Downloaded from http://cshperspectives.cshlp.org/ on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press S.M. King termediate chain that consists of an amino-ter- rently, there is little information on the precise minal thioredoxin module followed by two or functional interplay among all of these mole- three nucleoside diphosphate kinase catalytic cules. Various dynein components are then spe- cores (Ogawa et al. 1996; Padma et al.
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