Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School
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 others. 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.
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