The Dynein Regulatory Complex is the Nexin Link and a Major Regulatory Node in Cilia and Flagella

Overview

Journal J Cell Biol

Specialty Cell Biology

Date 2009 Dec 17

PMID 20008568

Citations 172

Authors

Thomas Heuser

Milen Raytchev

Jeremy Krell

Mary E Porter

Daniela Nicastro

Affiliations

Soon will be listed here.

Abstract

Cilia and flagella are highly conserved microtubule (MT)-based organelles with motile and sensory functions, and ciliary defects have been linked to several human diseases. The 9 + 2 structure of motile axonemes contains nine MT doublets interconnected by nexin links, which surround a central pair of singlet MTs. Motility is generated by the orchestrated activity of thousands of dynein motors, which drive interdoublet sliding. A key regulator of motor activity is the dynein regulatory complex (DRC), but detailed structural information is lacking. Using cryoelectron tomography of wild-type and mutant axonemes from Chlamydomonas reinhardtii, we visualized the DRC in situ at molecular resolution. We present the three-dimensional structure of the DRC, including a model for its subunit organization and intermolecular connections that establish the DRC as a major regulatory node. We further demonstrate that the DRC is the nexin link, which is thought to be critical for the generation of axonemal bending.

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References

Smith E, Yang P . The radial spokes and central apparatus: mechano-chemical transducers that regulate flagellar motility. Cell Motil Cytoskeleton. 2003; 57(1):8-17. PMC: 1950942. DOI: 10.1002/cm.10155. View

Warner F . Ciliary inter-microtubule bridges. J Cell Sci. 1976; 20(1):101-14. DOI: 10.1242/jcs.20.1.101. View

Bower R, Vanderwaal K, OToole E, Fox L, Perrone C, Mueller J . IC138 defines a subdomain at the base of the I1 dynein that regulates microtubule sliding and flagellar motility. Mol Biol Cell. 2009; 20(13):3055-63. PMC: 2704157. DOI: 10.1091/mbc.e09-04-0277. View

Minoura I, Yagi T, Kamiya R . Direct measurement of inter-doublet elasticity in flagellar axonemes. Cell Struct Funct. 1999; 24(1):27-33. DOI: 10.1247/csf.24.27. View

Porter M, Sale W . The 9 + 2 axoneme anchors multiple inner arm dyneins and a network of kinases and phosphatases that control motility. J Cell Biol. 2000; 151(5):F37-42. PMC: 2174360. DOI: 10.1083/jcb.151.5.f37. View

McIntosh R, Nicastro D, Mastronarde D . New views of cells in 3D: an introduction to electron tomography. Trends Cell Biol. 2005; 15(1):43-51. DOI: 10.1016/j.tcb.2004.11.009. View

Sale W, Satir P . Direction of active sliding of microtubules in Tetrahymena cilia. Proc Natl Acad Sci U S A. 1977; 74(5):2045-9. PMC: 431070. DOI: 10.1073/pnas.74.5.2045. View

Smith E, Sale W . Regulation of dynein-driven microtubule sliding by the radial spokes in flagella. Science. 1992; 257(5076):1557-9. DOI: 10.1126/science.1387971. View

Fliegauf M, Benzing T, Omran H . When cilia go bad: cilia defects and ciliopathies. Nat Rev Mol Cell Biol. 2007; 8(11):880-93. DOI: 10.1038/nrm2278. View

10.

Piperno G, Mead K, Shestak W . The inner dynein arms I2 interact with a "dynein regulatory complex" in Chlamydomonas flagella. J Cell Biol. 1992; 118(6):1455-63. PMC: 2289619. DOI: 10.1083/jcb.118.6.1455. View

11.

Witman G, Plummer J, Sander G . Chlamydomonas flagellar mutants lacking radial spokes and central tubules. Structure, composition, and function of specific axonemal components. J Cell Biol. 1978; 76(3):729-47. PMC: 2110011. DOI: 10.1083/jcb.76.3.729. View

12.

Yeh S, Chen Y, Chang A, Ray R, She B, Lee W . Isolation and properties of Gas8, a growth arrest-specific gene regulated during male gametogenesis to produce a protein associated with the sperm motility apparatus. J Biol Chem. 2001; 277(8):6311-7. DOI: 10.1074/jbc.M106941200. View

13.

Piperno G . Regulation of dynein activity within Chlamydomonas flagella. Cell Motil Cytoskeleton. 1995; 32(2):103-5. DOI: 10.1002/cm.970320206. View

14.

Satir P . Studies on cilia. 3. Further studies on the cilium tip and a "sliding filament" model of ciliary motility. J Cell Biol. 1968; 39(1):77-94. PMC: 2107504. DOI: 10.1083/jcb.39.1.77. View

15.

Woolley D . Studies on the eel sperm flagellum. I. The structure of the inner dynein arm complex. J Cell Sci. 1997; 110 ( Pt 1):85-94. DOI: 10.1242/jcs.110.1.85. View

16.

Pettersen E, Goddard T, Huang C, Couch G, Greenblatt D, Meng E . UCSF Chimera--a visualization system for exploratory research and analysis. J Comput Chem. 2004; 25(13):1605-12. DOI: 10.1002/jcc.20084. View

17.

Bottcher B, Wynne S, Crowther R . Determination of the fold of the core protein of hepatitis B virus by electron cryomicroscopy. Nature. 1997; 386(6620):88-91. DOI: 10.1038/386088a0. View

18.

Mastronarde D, OToole E, McDonald K, McIntosh J, Porter M . Arrangement of inner dynein arms in wild-type and mutant flagella of Chlamydomonas. J Cell Biol. 1992; 118(5):1145-62. PMC: 2289584. DOI: 10.1083/jcb.118.5.1145. View

19.

Piperno G, Mead K, LeDizet M, Moscatelli A . Mutations in the "dynein regulatory complex" alter the ATP-insensitive binding sites for inner arm dyneins in Chlamydomonas axonemes. J Cell Biol. 1994; 125(5):1109-17. PMC: 2120054. DOI: 10.1083/jcb.125.5.1109. View

20.

Gibbons I . STUDIES ON THE PROTEIN COMPONENTS OF CILIA FROM TETRAHYMENA PYRIFORMIS. Proc Natl Acad Sci U S A. 1963; 50:1002-10. PMC: 221963. DOI: 10.1073/pnas.50.5.1002. View