Alan Brown, 2026
Who he is
Dr. Alan Brown joined the Department of Biological Chemistry and Molecular Pharmacology at Harvard Medical School in 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 postdoc with Dr. Matthew K. Higgins (now E. P. Abraham Chair of Structural Biology 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 and was promoted to Associate Professor in 2023.
What he does
The Brown laboratory is dedicated to uncovering the molecular mechanisms of eukaryotic cilia, with a focus on two fundamental questions: (1) How do motile cilia generate the rhythmic beating needed for fluid flow and cellular locomotion, and (2) How are proteins dynamically trafficked and assembled within cilia to build the structures necessary for motility and for the regulation of cilia-based signaling pathways. To address these questions, we have used cryo-EM approaches to determine structures of the molecular machineries responsible – the axoneme and the intraflagellar transport (IFT) complexes. Our research is ultimately driven by a desire to improve the diagnosis, understanding, and treatment of human ciliopathies – devastating and progressive conditions arising from defects in cilia structure and function. Ciliopathies are multi-system disorders that commonly present with respiratory disease due to compromised mucociliary flow, male infertility from defective sperm motility, laterality abnormalities from disrupted embryonic fluid flow, as well as skeletal abnormalities, kidney disease, and sensory defects caused by dysregulated ciliary signaling. Gaining a deeper understanding of ciliary mechanisms is therefore essential for the development of novel diagnostic tools and therapeutic strategies for these currently incurable conditions.
News from the Lab
Our most recent work focused on understanding how polyubiquitinated proteins are removed from cilia. Protein homeostasis within cilia is essential for proper signaling and cellular function, yet the mechanisms governing selective protein removal from these organelles have remained poorly understood. Although K63-linked polyubiquitination has emerged as a signal for ciliary protein export, the molecular machinery coupling ubiquitinated cargo to retrograde intraflagellar transport (IFT) trains was poorly defined. Our work addresses this gap by revealing that CFAP36, a conserved ciliary protein of previously unknown function, functions as a cilia-specific ubiquitin reader. Through an integrative approach combining proteomics, bioinformatics, biochemistry, live-cell imaging using TIRF microscopy, and in-silico protein-protein interaction screens, we demonstrated that CFAP36 forms a complex with the small GTPase ARL3 to bind polyubiquitinated proteins and physically link them to retrograde IFT trains for removal from cilia. The structural and biochemical analyses revealed an elegant molecular logic: CFAP36 employs a coincidence detection mechanism, simultaneously engaging two IFT subunits that become accessible only when IFT trains adopt their retrograde configuration, thereby ensuring directional selectivity for cargo export. Functional validation established CFAP36 as important for ciliary homeostasis and signaling. Genetic depletion of CFAP36 caused accumulation of K63-linked polyubiquitinated proteins within cilia and specifically disrupted Hedgehog signaling, a developmental pathway that relies on regulated retrieval of ubiquitinated receptors from cilia. These findings advance our understanding of how protein quality control and signal regulation are achieved within cilia and demonstrate how conformational changes in IFT trains create structural opportunities for cargo selectivity.
