The long-term goal of the Brown laboratory is to understand the structure and function of cilia (also known as eukaryotic flagella). Cilia are finger-like organelles that project from the surface of almost all eukaryotic cells. Motile cilia produce a driving force for locomotion or fluid flow, whereas immotile cilia are involved in developmental signaling and sensory perception. Genetic disorders, collectively known as ciliopathies, can affect both types of cilia and lead to infertility, respiratory disease, blindness and polycystic kidney disease, among other symptoms. As treatment for ciliopathies is predominantly palliative, understanding how cilia are made and what goes wrong in ciliopathies is of vital importance.
Central to all cilia is the axoneme, one of the most geometrically complex and structurally conserved macromolecular machines found in nature. In motile cilia, the axoneme is responsible for generating motility. Using high-resolution electron cryomicroscopy (cryo-EM) and electron cryotomography (cryo-ET) we aim to resolve this beautiful yet complicated structure in atomic detail. Recently, we have determined structures and built detailed atomic models of ciliary doublet microtubules, radial spoke complexes and axonemal dyneins.
The doublet microtubules of the axoneme are also exploited as a molecular track for the transport of proteins within cilia, in a process known as intraflagellar transport. The Brown lab is using biochemistry and structural methods to understand the interplay between microtubules, motor proteins, adaptor complexes and their cargoes, and the role of these processes in establishing and maintaining neuronal signaling pathways. An example of our recent work in this area is the cryo-EM structure of the mammalian BBSome complex, which transports transmembrane proteins in the cilium.
We are also interested in developing new methods to accelerate and improve cryo-EM structure determination. In particular, how we can improve the interpretation of cryo-EM density maps with all-atom models and make these models as accurate as possible.
Dr. Alan Brown has been an Assistant Professor of Biological Chemistry and Molecular Pharmacology at Harvard Medical School since fall 2017. Dr. Brown received his Ph.D. degree from the University of Cambridge in 2010 where he studied X-ray crystallography under Dr. Tom L. Blundell. He then completed a short postdoc with Dr. Matthew K. Higgins (now Professor of Molecular Parasitology at the University of Oxford) while his laboratory was located at the University of Cambridge. In 2012, he joined Dr. Venki Ramakrishnan’s group at the Medical Research Council Laboratory of Molecular Biology (MRC-LMB) as a Career Development Fellow to study ribosome structure and function by cryo-EM. Dr. Brown was named a Pew Biomedical Scholar in 2019.
Mechanism of IFT-A polymerization into trains for ciliary transport.
Meleppattu S, Zhou H, Dai J, Gui M, Brown A
De novo identification of mammalian ciliary motility proteins using cryo-EM
Gui M, Farley H, Anujan P, Anderson JR, Maxwell DW, Whitchurch JB, Botsch JJ, Qui T, Meleppattu S, Singh SK, Zhang Q, Thompson J, Lucas JS, Bingle CD, Norris DP, Roy S, Brown A.
Structures of radial spokes and associated complexes important for ciliary motility
Gui M, Ma M, Sze-Tu E, Wang X, Koh F, Zhong ED, Berger B, Davis JH, Dutcher SK, Zhang R, Brown A.
Nat. Struct. Mol. Biol.; doi: https://doi.org/10.1038/s41594-020-00530-0
Structure and activation mechanism of the BBSome membrane protein trafficking complex
Singh SK, Gui M, Koh F, Yip MCJ, Brown A
Structure of the decorated ciliary doublet microtubule
Ma M, Stoyanova M, Rademacher G, Dutcher SK, Brown A, Zhang R
Cell; 179(4), 909-922
To see the full list of publications: https://brown.hms.harvard.edu/publications