Molecular Biology Faculty
Frederick M. Hughson
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 Hughson Research Lab |
 (609) 258-4982 |
 Schultz Laboratory, 215 |
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Lab (609) 258-5069 |
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Faculty Assistant
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Anna Schmedel
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(609) 258-5028 |
Research Focus
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.
Selected Publications
Hughson FM. (20130) Neuroscience. Chaperones that SNARE neurotransmitter release. Science. 339: 406-7. Pubmed
McMahon C, Studer SM, Clendinen C, Dann GP, Jeffrey PD, Hughson FM. (2012) The structure of Sec12 implicates potassium ion coordination in Sar1 activation. J Biol Chem. 287: 43599-606. Pubmed
Chen G, Swem LR, Swem DL, Stauff DL, O'Loughlin CT, Jeffrey PD, Bassler BL, Hughson FM. (2011) A strategy for antagonizing quorum sensing. Mol Cell. 42: 199-209. PubMed
Lees JA, Yip CK, Walz T, Hughson FM. (2010) Molecular organization of the COG vesicle tethering complex. Nat Struct Mol Biol. 17: 1292-1297. PubMed
Yu IM, Hughson FM. (2010) Tethering factors as organizers of intracellular vesicular traffic. Annu Rev Cell Dev Biol. 26: 137-156. PubMed
Hughson FM. (2010) Copy coats: COPI mimics clathrin and COPII. Cell. 142: 19-21. PubMed
Hughson FM, Reinisch KM. (2010) Structure and mechanism in membrane trafficking. Curr Opin Cell Biol. 22: 454-460. PubMed
Ren Y, Yip CK, Tripathi A, Huie D, Jeffrey PD, Walz T, Hughson FM. (2009) A structure-based mechanism for vesicle capture by the multisubunit tethering complex Dsl1. Cell. 139: 1119-1129. PubMed
Kelly RC, Bolitho ME, Higgins DA, Lu W, Ng WL, Jeffrey PD, Rabinowitz JD, Semmelhack MF, Hughson FM, Bassler BL. (2009) The Vibrio cholerae quorum-sensing autoinducer CAI-1: analysis of the biosynthetic enzyme CqsA. Nat Chem Biol. 5: 891-895. PubMed
Richardson BC, Smith RD, Ungar D, Nakamura A, Jeffrey PD, Lupashin VV, Hughson FM. (2009) Structural basis for a human glycosylation disorder caused by mutation of the COG4 gene. Proc Natl Acad Sci 106: 13329-13334. PubMed
Tripathi A, Ren Y, Jeffrey PD, Hughson FM. (2009) Structural characterization of Tip20p and Dsl1p, subunits of the Dsl1p vesicle tethering complex. Nat Struct Mol Biol. 16: 114-123. PubMed
Hughson FM. (2008) Both layers of the COPII coat come into view. Cell 134: 384-385. PubMed
Neiditch MB, Hughson FM. (2007) The regulation of histidine sensor kinase complexes by quorum sensing signal molecules. Methods Enzymol. 423: 250-263. PubMed
Cavanaugh LF, Chen X, Richardson BC, Ungar D, Pelczer I, Rizo J, Hughson FM. (2007) Structural analysis of conserved oligomeric golgi complex subunit 2. J Biol Chem 282: 23418-23426. PubMed
Neiditch MB, Federle MJ, Pompeani AJ, Kelly RC, Swem DL, Jeffrey PD, Bassler BL, Hughson FM. (2006) Ligand-induced asymmetry in histidine sensor kinase complex regulates quorum sensing. Cell 126: 1095-1108. PubMed
Ungar D, Oka T, Krieger M, Hughson FM. (2006) Retrograde transport on the COG railway. Trends Cell Biol 16: 113-120. PubMed
Ungar D, Oka T, Vasile E, Krieger M, Hughson FM. (2005) Subunit architecture of the conserved oligomeric Golgi complex. J Biol Chem 280: 32729-32735. PubMed
Oka T, Vasile E, Penman M, Novina CD, Dykxhoorn DM, Ungar D, Hughson FM, Krieger M. (2005) Genetic analysis of the subunit organization and function of the conserved oligomeric golgi (COG) complex: studies of COG5- and COG7-deficient mammalian cells. J Biol Chem 280: 32736-32745. PubMed
Neiditch MB, Federle MJ, Miller ST, Bassler BL, Hughson FM. (2005) Regulation of LuxPQ receptor activity by the quorum-sensing signal autoinducer-2. Mol Cell 18: 507-518. PubMed
Oka T, Ungar D, Hughson FM, Krieger M. (2004) The COG and COPI complexes interact to control the abundance of GEARs, a subset of Golgi integral membrane proteins. Mol Biol Cell 15: 2423-2435. PubMed
Miller ST, Xavier KB, Campagna SR, Taga ME, Semmelhack MF, Bassler BL, Hughson FM. (2004) Salmonella typhimurium recognizes a chemically distinct form of the bacterial quorum-sensing signal AI-2. Mol Cell 15: 677-687. PubMed
Zweifel ME, Leahy DJ, Hughson FM, Barrick D. (2003) Structure and stability of the ankyrin domain of the Drosophila Notch receptor. Protein Sci 12: 2622-2632. PubMed
Ungar D and Hughson FM. (2003) SNARE protein structure and function. Annu Rev Cell Dev Biol 19: 493-517. PubMed
Munson M, Hughson FM. (2002) Conformational regulation of SNARE assembly and disassembly in vivo. J Biol Chem 277: 9375-9381. PubMed
Chen X, Schauder S, Potier N, Van Dorsselaer A, Pelczer I, Bassler BL, Hughson FM. (2002) Structural identification of a bacterial quorum-sensing signal containing boron. Nature 415: 545-549. PubMed
Barrick D, Hughson FM. (2002) Irreversible assembly of membrane fusion machines. Nat Struct Biol 9: 78-80. PubMed
