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Cytoskeleton (Hoboken)
2018 Aug 01;758:372-381. doi: 10.1002/cm.21483.
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Turning dyneins off bends cilia.
King SM
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Ciliary and flagellar motility is caused by the ensemble action of inner and outer dynein arm motors acting on axonemal doublet microtubules. The switch point or switching hypothesis, for which much experimental and computational evidence exists, requires that dyneins on only one side of the axoneme are actively working during bending, and that this active motor region propagate along the axonemal length. Generation of a reverse bend results from switching active sliding to the opposite side of the axoneme. However, the mechanochemical states of individual dynein arms within both straight and curved regions and how these change during beating has until now eluded experimental observation. Recently, Lin and Nicastro used high-resolution cryo-electron tomography to determine the power stroke state of dyneins along flagella of sea urchin sperm that were rapidly frozen while actively beating. The results reveal that axonemal dyneins are generally in a pre-power stroke conformation that is thought to yield a force-balanced state in straight regions; inhibition of this conformational state and microtubule release on specific doublets may then lead to a force imbalance across the axoneme allowing for microtubule sliding and consequently the initiation and formation of a ciliary bend. Propagation of this inhibitory signal from base-to-tip and switching the microtubule doublet subsets that are inhibited is proposed to result in oscillatory motion.
Figure 1. Dynein organization and power stroke structural transitions. This diagram illustrates the four major transitions that occur during the dynein mechanochemical cycle. Dynein is anchored to the Aâ€tubule (not shown) via the Nâ€terminal domain and IC/LC complex. Nucleotide binding at AAA1 converts the motor to the preâ€power stroke I conformation in which the linker (purple) undergoes an almost 90° bend causing the AAA ring to swing, simultaneously the microtubuleâ€binding domain (MTBD) adopts a low affinity conformation and releases the Bâ€tubule. Following nucleotide hydrolysis, the MTBD transitions to a high affinity state and rebinds the microtubule at a new site. Phosphate release triggers the return of the linker to its original unbent state and thus drives the attached microtubule toward the axonemal distal tip. Finally, ADP departs the active site leaving the AAA1 nucleotide pocket empty and the HC capable of undergoing another mechanochemical cycle. HC, heavy chain; IC, intermediate chain; LC, light chain [Color figure can be viewed at http://wileyonlinelibrary.com]
Figure 2. Arrangement and interconnectivity of axonemal motors and regulators. (a) Diagram of the ciliary axonemal crossâ€section indicating the key structural elements including the A†and Bâ€tubules of the outer doublet microtubules, the inner and outer dynein arms, nexinâ€dynein regulatory complex, radial spokes, central pair microtubule complex, and the bridge structure that spans the gap between doublets 5 and 6. Based on analysis of orthologous components in Chlamydomonas, within the sea urchin outer dynein arm the HCs are arranged with the β HC outermost. (b) diagram illustrating the general arrangement along the axonemal long axis of the inner and outer arm dynein motors and the key regulatory components that control their activity in sea urchin sperm; unlike opisthokonts, in Chlamydomonas the outer arms have three HCs and RS3 is truncated lacking the spoke head and most of the stalk. All these components are tightly associated with Aâ€tubule (yellow) and the orientation with respect to the ciliary base and tip is indicated. Inner arm I1/f consists of the 1α and 1β HC motors (indicated as 1α and 1β) and the IC/LC complex that contains the key regulator IC138. The motor domains of the I1/f inner arm dynein are attached to the Aâ€tubule via the tether/tether head complex (red) that restricts their motion. Dyneins transiently interact with the Bâ€tubule (not shown) in an ATPâ€dependent manner to generate force, while the Nâ€DRC provides a nucleotideâ€independent linkage that connects adjacent doublets and acts to resist sliding. This converts the dyneinâ€generated unidirectional force vector into a microtubule bend. The radial spokes transduce mechanical signals from the central pair microtubule complex (not shown) to the inner arm system. Not shown is the calmodulin spoke complex that interconnects RS2, RS3, and the Nâ€DRC. Linkers (blue) allow signal transmission from inner arm I1/f and the Nâ€DRC (green) to the outer arm dyneins. HC, heavy chain; IC, intermediate chain; LC, light chain; Nâ€DRC, nexinâ€dynein regulatory complex [Color figure can be viewed at http://wileyonlinelibrary.com]
Figure 3. Dynein power stroke transitions during oscillatory beating. Top – Diagram of a swimming sea urchin sperm. The symmetric flagella waveform propagates from base to tip. Regions corresponding to the principal bend (light pink), reverse bend (light green), and the straight region (light yellow) between them are boxed. Also shown (arrows) are the “principal bend to straight region†and “straight region to reverse bend†transition segments where only some inner arms are in the inactive conformation. Bottom – Diagrams of axonemal crossâ€sections showing the status of individual dynein motors on each doublet in EHNAâ€inhibited sperm, principal and reverse bends, straight intervening region and the transitional segments; blue – preâ€power stroke, purple – postâ€power stroke, red – inhibited (weakly bound or microtubuleâ€detached) state, pink – bridge structure between doublets 5 and 6, blueâ€gray – Nâ€DRC, yellow – radial spokes. In bends, both inner and outer arms on doublets 2–4 or 7–9 are in the inhibited state. In the straight region, most dyneins are in a preâ€power stroke conformation, while in transitions between bends and straight segments, only inner arm subsets are inactivated. EHNA, erythoâ€9â€(2â€hydroxynonyl)adenine; Nâ€DRC, nexinâ€dynein regulatory complex. [Color figure can be viewed at http://wileyonlinelibrary.com]
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