Professor of Molecular Biology

Contact

hughson@princeton.edu
609-258-4982
609-258-6730
Schultz Laboratory, 215
Hughson Lab

Faculty Assistant

Karen Plantarich

Education

B.S., Molecular Biophysics & Biochemistry, Yale University
Ph.D., Biochemistry, Stanford University

Curriculum Vitae

Research Area

Biochemistry, Biophysics & Structural Biology

Research Focus

Structural cell biology



Research
Selected Publications
Honors & Awards

Intracellular Trafficking

One major focus of the research in my group is to understand the protein machinery that generates the interior architecture of cells by guiding the movement and fusion of intracellular transport vesicles. All eukaryotic cells contain a profusion of membrane-bounded compartments. Traffic among these compartments is brisk. Cargo is transported in membrane vesicles that bud from one compartment, travel through the cell, and deliver their contents by fusing with another compartment. Underlying this intricate choreography is a set of proteins and protein complexes responsible for the creation, movement, docking, and fusion of vesicles. Our lab seeks to understand the design principles that endow these protein nanomachines with the ability to manipulate membrane vesicles, thereby powering a bustling intracellular transportation network.
Several of our current projects involve structural and mechanistic studies of large multi-subunit protein complexes that orchestrate the docking and fusion of transport vesicles. These complexes guide cargo-laden vesicles to their destinations and coordinate the activities of other components of the trafficking machinery, including the 'SNARE' proteins that catalyze membrane fusion itself. We are investigating the structure and function of these complexes using an array of technologies including x-ray crystallography, electron microscopy, site-directed mutagenesis, in vitro reconstitution, and a suite of spectroscopic techniques.
The initial recognition between a vesicle and its membrane target, on the other hand, is mediated by large protein complexes called tethering factors. Tethering factors act upstream of SNARE complex assembly and play key roles in determining the specificity of trafficking. Because little is known about the structures of tethering factors or the mechanism(s) by which they act, we have recently initiated biochemical and biophysical studies of these key protein complexes.

Quorum Sensing

A second major focus within our group is bacteria, and the remarkable finding that these single-celled organisms communicate with one another by emitting and receiving small-molecule signals. We are interested in cataloging the signal molecules and in understanding their biosynthesis and detection. Moreover, since bacteria often respond to these signals in undesirable ways – like forming antibiotic-resistant biofilms or mounting an attack on a human host – we are interested in discovering and characterizing molecules that interfere with bacterial communication. We are investigating these issues using a range of biochemical and biophysical approaches. For example, we are attempting to determine the crystal structures of the enzymes responsible for synthesizing the signal molecules, and of the receptors responsible for detecting them. We have also begun to identify antagonists – molecules that inhibit signaling – and we are interested in using biochemical and structural methods to figure out how they work and how they might be improved by rational design. Finally, in collaboration with other Princeton labs in the molecular biology, chemistry, and physics departments, we are trying to understand how bacteria integrate the information they receive via multiple different signal molecules to craft an appropriate response.




Zhang Y, Hughson FM. Chaperoning SNARE Folding and Assembly. Annu Rev Biochem. 2021 ;90:581-603. PubMed
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Wong S, Hepowit NL, Port SA, Yau RG, Peng Y, Azad N, et al. Cargo Release from Myosin V Requires the Convergence of Parallel Pathways that Phosphorylate and Ubiquitylate the Cargo Adaptor. Curr Biol. 2020 ;30(22):4399-4412.e7. PubMed
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Eisemann TJ, Allen F, Lau K, Shimamura GR, Jeffrey PD, Hughson FM. The Sec1/Munc18 protein Vps45 holds the Qa-SNARE Tlg2 in an open conformation. Elife. 2020 ;9. PubMed
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Travis SM, DAmico K, Yu I-M, McMahon C, Hamid S, Ramirez-Arellano G, et al. Structural basis for the binding of SNAREs to the multisubunit tethering complex Dsl1. J Biol Chem. 2020 ;295(30):10125-10135. PubMed
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Travis SM, Kokona B, Fairman R, Hughson FM. Roles of singleton tryptophan motifs in COPI coat stability and vesicle tethering. Proc Natl Acad Sci U S A. 2019 ;116(48):24031-24040. PubMed
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Brose N, Brunger A, Cafiso D, Chapman ER, Diao J, Hughson FM, et al. Synaptic vesicle fusion: today and beyond. Nat Struct Mol Biol. 2019 ;26(8):663-668. PubMed
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Paczkowski JE, McCready AR, Cong J-P, Li Z, Jeffrey PD, Smith CD, et al. An Autoinducer Analogue Reveals an Alternative Mode of Ligand Binding for the LasR Quorum-Sensing Receptor. ACS Chem Biol. 2019 ;14(3):378-389. PubMed
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Jiao J, He M, Port SA, Baker RW, Xu Y, Qu H, et al. Munc18-1 catalyzes neuronal SNARE assembly by templating SNARE association. Elife. 2018 ;7. PubMed
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Ha JYong, Chou H-T, Ungar D, Yip CK, Walz T, Hughson FM. Molecular architecture of the complete COG tethering complex. Nat Struct Mol Biol. 2016 ;23(8):758-60. PubMed
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Baker RW, Hughson FM. Chaperoning SNARE assembly and disassembly. Nat Rev Mol Cell Biol. 2016 ;17(8):465-79. PubMed
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Boyaci H, Shah T, Hurley A, Kokona B, Li Z, Ventocilla C, et al. Structure, Regulation, and Inhibition of the Quorum-Sensing Signal Integrator LuxO. PLoS Biol. 2016 ;14(5):e1002464. PubMed
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Baker RW, Jeffrey PD, Zick M, Phillips BP, Wickner WT, Hughson FM. A direct role for the Sec1/Munc18-family protein Vps33 as a template for SNARE assembly. Science. 2015 ;349(6252):1111-4. PubMed
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Suckling RJ, Poon PPhi, Travis SM, Majoul IV, Hughson FM, Evans PR, et al. Structural basis for the binding of tryptophan-based motifs by δ-COP. Proc Natl Acad Sci U S A. 2015 ;112(46):14242-7. PubMed
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Ha JYong, Pokrovskaya ID, Climer LK, Shimamura GR, Kudlyk T, Jeffrey PD, et al. Cog5-Cog7 crystal structure reveals interactions essential for the function of a multisubunit tethering complex. Proc Natl Acad Sci U S A. 2014 ;111(44):15762-7. PubMed
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Rogers JV, McMahon C, Baryshnikova A, Hughson FM, Rose MD. ER-associated retrograde SNAREs and the Dsl1 complex mediate an alternative, Sey1p-independent homotypic ER fusion pathway. Mol Biol Cell. 2014 ;25(21):3401-12. PubMed
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Bharucha N, Liu Y, Papanikou E, McMahon C, Esaki M, Jeffrey PD, et al. Sec16 influences transitional ER sites by regulating rather than organizing COPII. Mol Biol Cell. 2013 ;24(21):3406-19. PubMed
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Chen G, Swem LR, Swem DL, Stauff DL, O'Loughlin CT, Jeffrey PD, et al. A strategy for antagonizing quorum sensing. Mol Cell. 2011 ;42(2):199-209. PubMed
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Kelly RC, Bolitho ME, Higgins DA, Lu W, Ng W-L, Jeffrey PD, et al. The Vibrio cholerae quorum-sensing autoinducer CAI-1: analysis of the biosynthetic enzyme CqsA. Nat Chem Biol. 2009 ;5(12):891-5. PubMed
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Neiditch MB, Federle MJ, Pompeani AJ, Kelly RC, Swem DL, Jeffrey PD, et al. Ligand-induced asymmetry in histidine sensor kinase complex regulates quorum sensing. Cell. 2006 ;126(6):1095-108. PubMed
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Neiditch MB, Federle MJ, Miller ST, Bassler BL, Hughson FM. Regulation of LuxPQ receptor activity by the quorum-sensing signal autoinducer-2. Mol Cell. 2005 ;18(5):507-18. PubMed
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Miller ST, Xavier KB, Campagna SR, Taga ME, Semmelhack MF, Bassler BL, et al. Salmonella typhimurium recognizes a chemically distinct form of the bacterial quorum-sensing signal AI-2. Mol Cell. 2004 ;15(5):677-87. PubMed
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Chen X, Schauder S, Potier N, Van Dorsselaer A, Pelczer I, Bassler BL, et al. Structural identification of a bacterial quorum-sensing signal containing boron. Nature. 2002 ;415(6871):545-9. PubMed
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2015

President's Award for Distinguished Teaching, Princeton University