About

Susan Marqusee is a Professor at the University of California Berkeley, affiliated with the Department of Molecular and Cell Biology and the California Institute for Quantitative & Biological Sciences. She serves as the Principal Investigator of the Marqusee Lab, where her research focuses on understanding the molecular mechanisms underlying protein folding, stability, and function. Her work aims to elucidate how proteins maintain their structure and activity under various cellular conditions, which has implications for understanding diseases related to protein misfolding and developing therapeutic strategies.

Research topics

• Biology
• Biophysics
• Biochemistry
• Genetics
• Chemistry
• Cell biology
• Virology
• Medicine
• Crystallography
• Computational biology
• Stereochemistry

Selected publications

• “Design principles of a membrane-spanning ubiquitin ligase”

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-09-16 · 2 citations

  preprintOpen access

  Summary Receptor-type E3 ubiquitin ligases are membrane-spanning assemblies that enable extracellular signals to directly control ubiquitylation in the cytoplasm. Despite playing widespread roles in tissue patterning and homeostasis, metabolism, and immunity, their structures and mechanisms remain poorly understood. Using cryo-electron microscopy, integrated with biophysical and functional studies, we visualized an E3 complex composed of two transmembrane proteins, MEGF8 and MOSMO, and the intracellular RING-family protein MGRN1. This MEGF8-MOSMO-MGRN1 (MMM) complex regulates left-right patterning of the body axis and the development of multiple organs, partly by attenuating signaling through the Hedgehog pathway. We find that the MMM complex functions like a fishing pole: a long, flexible helix attached to a membrane platform suspends an activated and precisely oriented RING domain—like a fishhook—to ubiquitylate the cytoplasmic surfaces of target receptors. Our structure explains how mutations in MEGF8 cause multi-organ birth defects in humans and defines a paradigm for receptor regulation by ubiquitylation.

  PublisherOA PDFDOI

• BPS2025 - X-ray footprinting/mass spectrometry offers a new, detailed view of intrinsically disordered protein structural ensembles

  Biophysical Journal · 2025-02-01

  articleSenior author
  PublisherDOI

• Domain coupling in activation of a family C GPCR

  Nature Chemical Biology · 2025-04-25 · 3 citations

  articleOpen access

  The G protein-coupled metabotropic glutamate receptors form homodimers and heterodimers with highly diverse responses to glutamate and varying physiological functions. We employ molecular dynamics, single-molecule spectroscopy and hydrogen-deuterium exchange to dissect the activation pathway triggered by glutamate. We find that activation entails multiple loosely coupled steps, including formation of an agonist-bound, pre-active intermediate whose transition to active conformations forms dimerization interface contacts that set efficacy. The agonist-bound receptor populates at least two additional intermediates en route to G protein-coupling conformations. Sequential transitions into these states act as 'gates', which attenuate the effects of glutamate. Thus, the agonist-bound receptor is remarkably dynamic, with low occupancy of G protein-coupling conformations, providing considerable headroom for modulation by allosteric ligands. Sequence variation within the dimerization interface, as well as altered conformational coupling in receptor heterodimers, may contribute to precise decoding of glutamate signals over broad spatial and temporal scales.

  PublisherOA PDFDOI

• BPS2025 - A helical fulcrum in eIF2B coordinates the allosteric regulation of stress signaling

  Biophysical Journal · 2025-02-01

  article
  PublisherDOI

• NUB1 traps unfolded FAT10 for ubiquitin-independent degradation by the 26S proteasome

  Nature Structural & Molecular Biology · 2025-04-11 · 11 citations

  articleOpen access

  The ubiquitin-like modifier FAT10 targets hundreds of proteins in the mammalian immune system to the 26S proteasome for degradation. This degradation pathway requires the cofactor NUB1, yet the underlying mechanisms remain unknown. Here, we reconstituted a minimal in vitro system with human components and revealed that NUB1 uses the intrinsic instability of FAT10 to trap its N-terminal ubiquitin-like domain in an unfolded state and deliver it to the 26S proteasome for engagement, allowing the degradation of FAT10-ylated substrates in a ubiquitin-independent and p97-independent manner. Using hydrogen-deuterium exchange, structural modeling and site-directed mutagenesis, we identified the formation of an intricate complex with FAT10 that activates NUB1 for docking to the 26S proteasome, and our cryo-EM studies visualized the highly dynamic NUB1 complex bound to the proteasomal Rpn1 subunit during FAT10 delivery and the early stages of ATP-dependent degradation. These findings identified a previously unknown mode of cofactor-mediated, ubiquitin-independent substrate delivery to the 26S proteasome that relies on trapping partially unfolded states for engagement by the proteasomal ATPase motor.

  PublisherOA PDFDOI

• The Interplay of Furin Cleavage and D614G in Modulating SARS-CoV-2 Spike Protein Dynamics

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-28 · 3 citations

  preprintOpen accessSenior authorCorresponding

  We report a detailed analysis of the full-length SARS-CoV-2 spike dynamics within a native-like membrane environment and variants inaccessible to studies on soluble constructs by conducting hydrogen-deuterium exchange mass spectrometry (HDX-MS) on enveloped virus-like particles (eVLPs) displaying various spike constructs. We find that the previously identified open-interface trimer conformation is sampled in all eVLP-displayed spike variants studied including sequences from engineered vaccine constructs and native viral sequences. The D614G mutation, which arose early in the pandemic, favors the canonical 'closed-interface' prefusion conformation, potentially mitigating premature S1 shedding in the presence of a cleaved furin site and providing an evolutionary advantage to the virus. Remarkably, furin cleavage at the S1/S2 boundary allosterically increases the flexibility of the S2' site, which may facilitate increased TMPRSS2 processing, enhancing viral infectivity. The use of eVLPs in HDX-MS studies provides a powerful platform for studying viral and membrane proteins in near-native environments.

  PublisherOA PDFDOI

• BPS2025 - A helical fulcrum in eIF2B coordinates allosteric regulation of stress signaling

  Biophysical Journal · 2025-02-01

  article
  PublisherDOI

• BPS2025 - X-ray footprinting/mass spectrometry offers a new, detailed view of intrinsically disordered protein structural ensembles

  Biophysical Journal · 2025-02-01

  articleSenior author
  PublisherDOI

• Ultrapotent SARS coronavirus-neutralizing single-domain antibodies that clamp the spike at its base

  Nature Communications · 2025-05-30 · 8 citations

  articleOpen access

  Therapeutic monoclonal antibodies can prevent severe disease in SARS-CoV-2 exposed individuals. However, currently circulating virus variants have evolved to gain significant resistance to nearly all neutralizing human immune system-derived therapeutic monoclonal antibodies that had previously been emergency-authorized for use in the clinic. Here, we describe the discovery of a panel of single-domain antibodies (VHHs) directed against the spike protein S2 subunit that broadly neutralize SARS-CoV-1 and −2 with unusually high potency. One of these VHHs tightly clamps the spike’s monomers at a highly conserved, quaternary epitope in the membrane proximal part of the trimeric Heptad Repeat 2 (HR2) coiled-coil, thereby locking the HR2 in its prefusion conformation. Low dose systemic administration of a VHH-human IgG1 Fc fusion prevented SARS-CoV-2 infection in two animal models. Pseudovirus escape selection experiments demonstrate that the very rare escape variants are rendered almost non-infectious. This VHH-based antibody with a highly potent mechanism of antiviral action forms the basis for a new class of pan-sarbecovirus neutralizing biologics, which are currently under development. In addition, the unique quaternary binding mode of the VHHs to the prefusion HR2 could be exploited for other class I fusion proteins. Here the authors characterize a single-domain antibody that broadly neutralizes SARS-CoV-2 variants with high potency by targeting the heptad repeat 2 (HR2) coiled coil, conserved in sarbecoviruses. Binding to its quaternary epitope blocks membrane fusion, by locking HR2 in its prefusion conformation.

  PublisherOA PDFDOI

• Cataract-prone variants of γD-crystallin populate a conformation with a partially unfolded N-terminal domain under native conditions

  Proceedings of the National Academy of Sciences · 2025-02-03 · 3 citations

  articleOpen accessSenior authorCorresponding

  Human γD-crystallin, a monomeric protein abundant in the eye lens nucleus, must remain stably folded for an individual's entire lifetime to avoid aggregation and protein deposition-associated cataract formation. γD-crystallin contains two homologous domains, an N-terminal domain (NTD) and a C-terminal domain (CTD), which interact via a hydrophobic interface. Several familial mutations in the gamma crystallin gene are linked to congenital early-onset cataract, most of which affect the NTD. Some of these, including V75D and W42R, are known to populate intermediates under partially denaturing conditions possessing a natively folded CTD and a completely unfolded NTD. We employed hydrogen-deuterium exchange mass spectrometry to probe the structural and energetic features of variants of γD-crystallin under both native and partially denaturing conditions. For V75D and W42R, we identify a species under native conditions that retains partial structure in the NTD and is structurally and energetically distinct from the intermediate populated under partially denaturing conditions. Residues at the NTD-CTD interface play crucial roles in stabilizing this intermediate, and disruption of interface contacts either by amino acid substitution or partial denaturation permits direct observation of two intermediates simultaneously. These data suggest that the intermediate identified under native conditions is accessed from the native state and not on the folding pathway. The intermediate we have identified here exposes hydrophobic amino acids that are buried in both the folded full-length protein and in the protein's stable isolated domains. Such nonnative exposure of a hydrophobic patch may play an important role in cataract formation.

  PublisherOA PDFDOI

Recent grants

• Single Molecule Studies of Protein Folding

  NSF · $1.2M · 2011–2017

• Project 2: Conformation and propagation of misfolded forms of tau and Abeta

  NIH · $84.7M · 1997–2026

• NIH Grant R29GM050945

  NIH · $517k · 1999

• Sequence and Environmental Determinants of the Protein Energy Landscape

  NIH · $7.6M · 1994–2023

• NIH Grant R01GM053321

  NIH · $474k · 1999

Frequent coauthors

• Carlos Bustamante

  University of California, Berkeley

  78 shared

• John Kuriyan

  Vanderbilt University

  58 shared

• Neel H. Shah

  Columbia University

  45 shared

• Christine L. Gee

  Howard Hughes Medical Institute

  45 shared

• Kambiz M. Hamadani

  California State University, San Marcos

  44 shared

• Shion A. Lim

  42 shared

• Jamie H. D. Cate

  University of California, Berkeley

  37 shared

• Emily J. Guinn

  Eli Lilly (United States)

  35 shared

Labs

• The Marqusee LabPI

  Not provided

Education

• PhD, Biochemistry

  Stanford University School of Medicine

  1990

• MD

  Stanford University School of Medicine

  1990

• AB, Physics and Chemistry

  Cornell University

  1982