About

Frederick M. Hughson is a Professor of Molecular Biology and serves as the Director of Undergraduate Studies in the Department of Molecular Biology. His research focuses on structural cell biology, particularly intracellular trafficking and bacterial quorum sensing. His group aims to understand the protein machinery that generates the interior architecture of cells by guiding the movement and fusion of intracellular transport vesicles. This involves studying the proteins and complexes responsible for vesicle creation, movement, docking, and fusion, using techniques such as x-ray crystallography, electron microscopy, site-directed mutagenesis, in vitro reconstitution, and spectroscopic methods. Additionally, Hughson's research explores bacterial communication through quorum sensing, investigating signal molecules, their biosynthesis, detection, and how bacteria respond to these signals. His work includes determining the structures of enzymes involved in signal synthesis and receptors responsible for detection, as well as identifying molecules that interfere with bacterial communication. His contributions have advanced understanding of the design principles of protein nanomachines involved in intracellular trafficking and bacterial signaling pathways.

Research topics

• Cell biology
• Biology
• Chemistry
• Biophysics
• Computational biology

Selected publications

• Discovery of a widespread chemical signalling pathway in the Bacteroidota

  Nature · 2025-08-20 · 7 citations

  article
  PublisherDOI

• Structure of a membrane tethering complex incorporating multiple SNAREs

  Nature Structural & Molecular Biology · 2024-01-09 · 15 citations

  articleOpen accessSenior author
  PublisherOA PDFDOI

• The machinery of vesicle fusion

  Current Opinion in Cell Biology · 2023-07-06 · 29 citations

  reviewOpen accessSenior authorCorresponding
  PublisherOA PDFDOI

• Structure of a Membrane Tethering Complex Incorporating Multiple SNAREs

  bioRxiv (Cold Spring Harbor Laboratory) · 2023-01-30 · 8 citations

  preprintOpen accessSenior authorCorresponding

  Most membrane fusion reactions in eukaryotic cells are mediated by membrane tethering complexes (MTCs) and SNARE proteins. MTCs are much larger than SNAREs and are thought to mediate the initial attachment of two membranes. Complementary SNAREs then form membrane-bridging complexes whose assembly draws the membranes together for fusion. Here, we present a cryo-EM structure of the simplest known MTC, the 255-kDa Dsl1 complex, bound to the two SNAREs that anchor it to the endoplasmic reticulum. N-terminal domains of the SNAREs form an integral part of the structure, stabilizing a Dsl1 complex configuration with remarkable and unexpected similarities to the 850-kDa exocyst MTC. The structure of the SNARE-anchored Dsl1 complex and its comparison with exocyst reveal what are likely to be common principles underlying MTC function. Our structure also implies that tethers and SNAREs can work together as a single integrated machine.

  PublisherOA PDFDOI

• Chaperoning SNARE Folding and Assembly

  Annual Review of Biochemistry · 2021-04-07 · 119 citations

  reviewOpen accessSenior author

  SNARE proteins and Sec1/Munc18 (SM) proteins constitute the core molecular engine that drives nearly all intracellular membrane fusion and exocytosis. While SNAREs are known to couple their folding and assembly to membrane fusion, the physiological pathways of SNARE assembly and the mechanistic roles of SM proteins have long been enigmatic. Here, we review recent advances in understanding the SNARE-SM fusion machinery with an emphasis on biochemical and biophysical studies of proteins that mediate synaptic vesicle fusion. We begin by discussing the energetics, pathways, and kinetics of SNARE folding and assembly in vitro. Then, we describe diverse interactions between SM and SNARE proteins and their potential impact on SNARE assembly in vivo. Recent work provides strong support for the idea that SM proteins function as chaperones, their essential role being to enable fast, accurate SNARE assembly. Finally, we review the evidence that SM proteins collaborate with other SNARE chaperones, especially Munc13-1, and briefly discuss some roles of SNARE and SM protein deficiencies in human disease.

  PublisherOA PDFDOI

• Structural basis for the binding of SNAREs to the multisubunit tethering complex Dsl1

  Journal of Biological Chemistry · 2020-05-14 · 21 citations

  articleOpen accessSenior author

  -ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-mediated membrane fusion in all eukaryotes. MTCs are thought to organize membrane trafficking by mediating the initial long-range interaction between a vesicle and its target membrane and promoting the formation of membrane-bridging SNARE complexes. Previously, we reported the structure of the yeast Dsl1 complex, the simplest known MTC, which is essential for coat protein I (COPI) mediated transport from the Golgi to the endoplasmic reticulum (ER). This structure suggests how the Dsl1 complex might tether a vesicle to its target membrane by binding at one end to the COPI coat and at the other to ER-associated SNAREs. Here, we used X-ray crystallography to investigate these Dsl1-SNARE interactions in greater detail. The Dsl1 complex comprises three subunits that together form a two-legged structure with a central hinge. We found that distal regions of each leg bind N-terminal Habc domains of the ER SNAREs Sec20 (a Qb-SNARE) and Use1 (a Qc-SNARE). The observed binding modes appear to anchor the Dsl1 complex to the ER target membrane while simultaneously ensuring that both SNAREs are in open conformations, with their SNARE motifs available for assembly. The proximity of the two SNARE motifs, and therefore their ability to enter the same SNARE complex, will depend on the relative orientation of the two Dsl1 legs. These results underscore the critical roles of SNARE N-terminal domains in mediating interactions with other elements of the vesicle docking and fusion machinery.

  PublisherOA PDFDOI

• The Sec1/Munc18 protein Vps45 holds the Qa-SNARE Tlg2 in an open conformation

  eLife · 2020-08-17 · 35 citations

  articleOpen accessSenior author

  Fusion of intracellular trafficking vesicles is mediated by the assembly of SNARE proteins into membrane-bridging complexes. SNARE-mediated membrane fusion requires Sec1/Munc18-family (SM) proteins, SNARE chaperones that can function as templates to catalyze SNARE complex assembly. Paradoxically, the SM protein Munc18-1 traps the Qa-SNARE protein syntaxin-1 in an autoinhibited closed conformation. Here we present the structure of a second SM-Qa-SNARE complex, Vps45-Tlg2. Strikingly, Vps45 holds Tlg2 in an open conformation, with its SNARE motif disengaged from its Habc domain and its linker region unfolded. The domain 3a helical hairpin of Vps45 is unfurled, exposing the presumptive R-SNARE binding site to allow template complex formation. Although Tlg2 has a pronounced tendency to form homo-tetramers, Vps45 can rescue Tlg2 tetramers into stoichiometric Vps45-Tlg2 complexes. Our findings demonstrate that SM proteins can engage Qa-SNAREs using at least two different modes, one in which the SNARE is closed and one in which it is open.

  PublisherDOI

• Author response: The Sec1/Munc18 protein Vps45 holds the Qa-SNARE Tlg2 in an open conformation

  2020-08-14

  peer-reviewOpen accessSenior author
  PublisherDOI

• Crystal structure of the SNARE Use1 bound to Dsl1 complex subunits Sec39 and Dsl1

  2020-03-29

  paratextSenior author
  PublisherDOI

• The Sec1/Munc18 protein Vps45 holds the Qa-SNARE Tlg2 in an open conformation

  bioRxiv (Cold Spring Harbor Laboratory) · 2020-07-02

  preprintOpen accessSenior authorCorresponding

  ABSTRACT Fusion of intracellular trafficking vesicles is mediated by the assembly of soluble N -ethylmaleimide-sensitive fusion protein receptors (SNAREs) to form membrane-bridging complexes. Also required for SNARE-mediated membrane fusion are Sec1/Munc18-family (SM) proteins, SNARE chaperones that can function as templates to catalyze SNARE complex assembly. In the paradigmatic structure of an SM–SNARE complex, Munc18-1 bound to the Qa-SNARE syntaxin 1, the SNARE protein is trapped in an autoinhibited closed conformation that prevents it from entering into SNARE complexes. Here, we present the structure of a second SM–Qa-SNARE complex, Vps45–Tlg2. Strikingly, Vps45 holds Tlg2 in an open conformation, with its SNARE motif disengaged from its three-helical Habc domain and its linker region unfolded. The domain 3a helical hairpin of Vps45 is unfurled, exposing the presumptive R-SNARE binding site to allow template complex formation. Tlg2 has a pronounced tendency to self-associate via its SNARE motif, and we demonstrate that Vps45 can rescue Tlg2 oligomers into stoichiometric Vps45–Tlg2 complexes. Our findings demonstrate that SM proteins can engage Qa-SNAREs using at least two different modes, one in which the SNARE is closed and one in which it is open.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R01NS038046

  NIH · $1.1M · 2003

• Manipulating Quorum Sensing to Control Bacterial Pathogenicity

  NIH · $398k · 2012–2014

• Structural Analysis of Membrane Tethering and Fusion Proteins

  NIH · $6.8M · 2005–2026

• Structure-Function Analysis of AI-2 Quorum Sensing

  NIH · $4.5M · 2003–2014

• NIH Grant R01GM059280

  NIH · $858k · 2003

Frequent coauthors

• Philip D. Jeffrey

  Princeton University

  20 shared

• Bonnie L. Bassler

  Howard Hughes Medical Institute

  13 shared

• Don C. Wiley

  Utah Department of Natural Resources

  11 shared

• Dániel Ungár

  University of York

  8 shared

• Robert L. Baldwin

  Brock University

  7 shared

• Richard W. Baker

  7 shared

• Robert Fairman

  6 shared

• Hui‐Ting Chou

  Amgen (United States)

  6 shared

Labs

• Hughson LabPI

Awards & honors

• 2015 President's Award for Distinguished Teaching, Princeton…