TY - JOUR
T1 - Axonemal structures reveal mechanoregulatory and disease mechanisms
AU - Walton, Travis
AU - Gui, Miao
AU - Velkova, Simona
AU - Fassad, Mahmoud R.
AU - Hirst, Robert A.
AU - Haarman, Eric
AU - O’Callaghan, Christopher
AU - Bottier, Mathieu
AU - Burgoyne, Thomas
AU - Mitchison, Hannah M.
AU - Brown, Alan
N1 - Funding Information: We thank C. Hogg and A. Rutman for TEM of nasal brushings, P. Griffin for acquiring high-speed video microscopy data, and R. K. Rai and P. Griffin for assistance in culturing human airway epithelial cells. Cryo-EM data were collected at the Harvard Center for Cryo-EM with assistance from S. Sterling, R. Walsh and M. Mayer. Cryo-EM data processing was supported by SBGrid (J. O’Connor, S. Rawson and W. Temple) and HMS Research Computing. T.W. was supported by a Helen Hay Whitney postdoctoral fellowship. M.G. was supported by a Charles A. King Trust postdoctoral fellowship. H.M.M. acknowledges funding from NIHR GOSH BRC, the Ministry of Higher Education in Egypt and MRC UCL Confidence in Concept (CiC7). A.B. was supported by grants from the National Institutes of Health (GM141109 and GM143183) and the Pew Charitable Trusts. Publisher Copyright: © 2023, The Author(s).
PY - 2023/6/15
Y1 - 2023/6/15
N2 - Motile cilia and flagella beat rhythmically on the surface of cells to power the flow of fluid and to enable spermatozoa and unicellular eukaryotes to swim. In humans, defective ciliary motility can lead to male infertility and a congenital disorder called primary ciliary dyskinesia (PCD), in which impaired clearance of mucus by the cilia causes chronic respiratory infections 1. Ciliary movement is generated by the axoneme, a molecular machine consisting of microtubules, ATP-powered dynein motors and regulatory complexes 2. The size and complexity of the axoneme has so far prevented the development of an atomic model, hindering efforts to understand how it functions. Here we capitalize on recent developments in artificial intelligence-enabled structure prediction and cryo-electron microscopy (cryo-EM) to determine the structure of the 96-nm modular repeats of axonemes from the flagella of the alga Chlamydomonas reinhardtii and human respiratory cilia. Our atomic models provide insights into the conservation and specialization of axonemes, the interconnectivity between dyneins and their regulators, and the mechanisms that maintain axonemal periodicity. Correlated conformational changes in mechanoregulatory complexes with their associated axonemal dynein motors provide a mechanism for the long-hypothesized mechanotransduction pathway to regulate ciliary motility. Structures of respiratory-cilia doublet microtubules from four individuals with PCD reveal how the loss of individual docking factors can selectively eradicate periodically repeating structures.
AB - Motile cilia and flagella beat rhythmically on the surface of cells to power the flow of fluid and to enable spermatozoa and unicellular eukaryotes to swim. In humans, defective ciliary motility can lead to male infertility and a congenital disorder called primary ciliary dyskinesia (PCD), in which impaired clearance of mucus by the cilia causes chronic respiratory infections 1. Ciliary movement is generated by the axoneme, a molecular machine consisting of microtubules, ATP-powered dynein motors and regulatory complexes 2. The size and complexity of the axoneme has so far prevented the development of an atomic model, hindering efforts to understand how it functions. Here we capitalize on recent developments in artificial intelligence-enabled structure prediction and cryo-electron microscopy (cryo-EM) to determine the structure of the 96-nm modular repeats of axonemes from the flagella of the alga Chlamydomonas reinhardtii and human respiratory cilia. Our atomic models provide insights into the conservation and specialization of axonemes, the interconnectivity between dyneins and their regulators, and the mechanisms that maintain axonemal periodicity. Correlated conformational changes in mechanoregulatory complexes with their associated axonemal dynein motors provide a mechanism for the long-hypothesized mechanotransduction pathway to regulate ciliary motility. Structures of respiratory-cilia doublet microtubules from four individuals with PCD reveal how the loss of individual docking factors can selectively eradicate periodically repeating structures.
UR - http://www.scopus.com/inward/record.url?scp=85160672190&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41586-023-06140-2
DO - https://doi.org/10.1038/s41586-023-06140-2
M3 - Article
C2 - 37258679
SN - 0028-0836
VL - 618
SP - 625
EP - 633
JO - NATURE
JF - NATURE
IS - 7965
ER -