About

Edward H. Egelman is a professor in the Department of Biochemistry and Molecular Genetics at the University of Virginia School of Medicine. He holds a BA in Physics and a PhD in Biophysics from Brandeis University, and completed postdoctoral training in Biophysics at the MRC Laboratory of Molecular Biology in Cambridge, UK. His research focuses on the structure and function of macromolecular assemblies, utilizing electron cryo-microscopy and three-dimensional reconstruction techniques. His work has historically concentrated on protein-DNA complexes and F-actin, with recent advancements enabling near-atomic resolution of many filamentous biological assemblies. Egelman's research explores themes such as the lability of quaternary structures, the impact of small sequence changes on protein assembly and evolution, and the extraordinary conservation of actin sequences over hundreds of millions of years. His studies have provided insights into how minor sequence variations can lead to significant structural and functional divergence, and how extensive allosteric networks within actin contribute to its remarkable properties. His contributions have advanced understanding of macromolecular complex architecture and dynamics, with implications for evolutionary biology and cellular function.

Research topics

• Biology
• Chemistry
• Biophysics
• Biochemistry
• Genetics
• Cell biology
• Evolutionary biology
• Anatomy
• Polymer chemistry
• Neuroscience

Selected publications

• Supramolecular Assembly of Collagen-Mimetic Peptide D-Periodic Fibrils and Nanoassemblies

  Biomacromolecules · 2026-03-26

  article

  The collagen triple helix assembles hierarchically into bundled oligomers, solvated networks, and fibers. Synthetic peptide assemblies, driven by supramolecular interactions, can form single triple helices through intrahelical amino acid pairs; however, the principles guiding interhelical associations into higher-order structures remain unclear. Here, we incorporate cation-π and electrostatic charge pairs to probe interhelical interactions and elucidate the mechanisms driving triple helix assembly into fibrils, nanotubes, and nanosheets. Introducing cation-π pairs into a fibrillating collagen mimetic resulted in D-periodic fibrils with pH-sensitive gelation. By alternating the presentation of electrostatic and cation-π pairs, the assembly of another D-periodic fibril featuring inner and outer triple-helical layers was resolved by cryo electron microscopy to a resolution of 8 Å. At physiological pH, antiparallel association of these triple helices leads to the formation of nanotubes. The packing behavior of triple helices correlates with the interhelical interactions, where parallel associations favor fibril formation and antiparallel interactions drive nanotube and nanosheet assembly. These self-assembling triple-helical peptides demonstrate how packing of higher-order structures can be tailored with supramolecular interactions and establish the relationship of different hierarchical collagen-mimetic assemblies as pH-dependent.

  PublisherDOI

• Structural determinants of endopilus assembly, stability and functional specificity in bacterial type II secretion

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-12

  articleOpen access

  Abstract Gram-negative bacteria employ the type II secretion system (T2SS) to transport folded protein effectors across the outer membrane. This multiprotein nanomachine assembles the endopilus, a periplasmic helical polymer composed of one major and four minor pilin subunits. Endopili are structurally related to type IV pili but exhibit distinct features including a conserved calcium-binding site stabilizing their major pilin subunits. Endopilus polymerisation is coupled to substrate translocation through a dedicated outer membrane channel. To investigate the structural basis of endopilus assembly, stability and functional specificity, we performed a comparative analysis of the Out T2SS from the plant pathogen Dickeya dadantii and the Pul T2SS from the human pathogen Klebsiella oxytoca. Although their major pilins OutG and PulG share over 77% sequence identity, these bacteria differ markedly in ecological niche and range of secreted effectors. We report here the NMR structure of calcium-bound OutG monomer and cryo-EM structures of OutG and PulG endopili at 3.6 Å resolution. The integration of structural, mutational, and biophysical analyses with in vivo assays, allowed us to identify the molecular determinants of secretion specificity and endopilus stability. These findings demonstrate how subtle sequence variations in conserved nanomachines have evolved to optimize their function and adapt to their local environments.

  PublisherOA PDFDOI

• Toll-like receptor signaling outcome is determined by the stoichiometry of the endogenous TRIFosome.

  Open MIND · 2026-02-03

  article

  Toll-like receptors (TLRs) drive innate immunity via assembly of macromolecular signal transduction platforms [supramolecular organizing centers (SMOCs)] coordinated by adaptor proteins such as Toll/interleukin-1 receptor (IL-1R) domain-containing adaptor-inducing interferon-β (TRIF), but whether oligomeric TRIFosomes form is unknown. Here, using cryo-electron microscopy and biophysical characterization of full-length TRIF in vitro, we show that it forms filamentous oligomers, which associate with the TRIF signaling partners receptor interacting protein 1 (RIP1) and RIP3 kinases, suggesting that oligomeric TRIFosomes could form. Endogenous TRIF, however, is predominantly monomeric in the absence of ligand, only forming TRIFosome oligomers in macrophages after stimulation of TLR4 or TLR3 when large, macromolecular signaling complexes form. TRIFosomes are fully formed 45 min after TLR3 or 60 min after TLR4 stimulation, commensurate with activation of nuclear factor κB in these cells. TLR3/4 activation triggers rapid interferon signaling prior to TRIFosome formation through monomeric TRIF, unexpectedly suggesting that a macromolecular platform of TRIF is not required to drive this signaling pathway. Collectively, these data show TRIFosome macromolecular platform formation and, unexpectedly, that TLR signaling can be SMOC-independent in addition to being SMOC-dependent.

  DOI

• Toll-like receptor signaling outcome is determined by the stoichiometry of the endogenous TRIFosome

  Science Advances · 2026-03-06

  articleOpen access

  Toll-like receptors (TLRs) drive innate immunity via assembly of macromolecular signal transduction platforms [supramolecular organizing centers (SMOCs)] coordinated by adaptor proteins such as Toll/interleukin-1 receptor (IL-1R) domain-containing adaptor-inducing interferon-β (TRIF), but whether oligomeric TRIFosomes form is unknown. Here, using cryo-electron microscopy and biophysical characterization of full-length TRIF in vitro, we show that it forms filamentous oligomers, which associate with the TRIF signaling partners receptor interacting protein 1 (RIP1) and RIP3 kinases, suggesting that oligomeric TRIFosomes could form. Endogenous TRIF, however, is predominantly monomeric in the absence of ligand, only forming TRIFosome oligomers in macrophages after stimulation of TLR4 or TLR3 when large, macromolecular signaling complexes form. TRIFosomes are fully formed 45 min after TLR3 or 60 min after TLR4 stimulation, commensurate with activation of nuclear factor κB in these cells. TLR3/4 activation triggers rapid interferon signaling prior to TRIFosome formation through monomeric TRIF, unexpectedly suggesting that a macromolecular platform of TRIF is not required to drive this signaling pathway. Collectively, these data show TRIFosome macromolecular platform formation and, unexpectedly, that TLR signaling can be SMOC-independent in addition to being SMOC-dependent.

  PublisherDOI

• BPS2026 – The prokaryotic flagellum: Rich stories in convergent and divergent evolution

  Biophysical Journal · 2026-02-01

  article1st authorCorresponding
  PublisherDOI

• Structural insights into the atypical filament assembly of pyrin domain-containing IFI16

  The EMBO Journal · 2025-11-05 · 3 citations

  articleOpen access

  Abstract In response to various intracellular stress or damage-associated signals, inflammasomes can be activated and trigger a pyroptotic cell death process through the sequential assembly of structurally compatible and interacting filamentous oligomers involving the pyrin domains (PYD) of important inflammasome components. The PYD-containing interferon-inducible protein 16 (IFI16) has been suggested as a viral DNA sensor that can induce inflammasome formation, but it also has other inflammasome-independent functions, including interferon production. Here, the cryo-EM structure of the filament assembled by the PYD of human IFI16 reveals a helical architecture distinct from inflammasome PYD filaments. In silico interface energy calculations suggest that the helical architecture of the IFI16 PYD filament prevents interactions with inflammasome PYD filaments. Biochemical and cell biology experiments consistently demonstrate that IFI16 does not directly interact with inflammasome pyrin domains. Together, our results provide insights into the structural basis of the inflammasome-independent functions of IFI16, and also show that strict architectural compatibility requirements for interactions contribute to the signal transduction specificity in inflammasome signaling.

  PublisherDOI

• A type IV pili-mediated mutualism between two co-resident temperate archaeal viruses and their host

  Cell Reports · 2025-06-20 · 3 citations

  articleOpen access

  Co-resident temperate viruses are ubiquitous in prokaryotes, which interact with each other and affect their shared host. However, how such virus-virus and virus-host interactions play out in Archaea remains largely unexplored. Here, we discover a tripartite mutualistic interaction among the co-existing temperate viruses SNJ1 and SNJ2 and their host, haloarchaeon Natrinema sp. J7. We find that the SNJ2 provirus encodes two type IV pilins (T4Ps), which hijack the host secretion machinery to assemble into distinct filaments on the host cell surface. The SNJ2-encoded pili are dispensable for the SNJ2 infection but serve as receptors for SNJ1. As a quid pro quo, SNJ1 enhances the replication of SNJ2. Furthermore, the viral pili are the dominant filaments on the cell surface and promote biofilm formation and motility of the host. A number of SNJ2-like proviruses harbor T4P genes, suggesting that T4P-mediated virus-virus and virus-host interactions are widespread in Haloarchaea.

  PublisherOA PDFDOI

• Author Correction: An extensive disulfide bond network prevents tail contraction in Agrobacterium tumefaciens phage Milano

  Nature Communications · 2025-08-07

  erratumOpen accessSenior author
  PublisherOA PDFDOI

• Tat-dependent bundling pilus of a halophilic archaeon assembles by a strand donation mechanism and facilitates biofilm formation

  Proceedings of the National Academy of Sciences · 2025-07-30 · 3 citations

  articleOpen accessSenior authorCorresponding

  Diverse extracellular filaments present on the surface of archaea mediate multiple key processes, such as motility, adhesion, and biofilm formation. Although several archaeal filament types have been characterized in considerable detail, many remain understudied, particularly those utilizing noncanonical secretion systems. Here, we describe the Tafi bundling pilus that facilitates biofilm formation in the haloarchaeon Natrinema sp. J7-2. Unlike previously characterized archaeal pili, Tafi is secreted via the twin-arginine translocation (Tat) pathway, which transports fully folded proteins across the cytoplasmic membrane. Structural analysis reveals that although Tafi pili assemble via a canonical strand-donation mechanism, the pilin subunit (TafE) adopts a distinct structural topology that sets it apart from the previously characterized Sec-dependent pilins that form bundling pili in archaea. Sequence analyses show that TafE homologs are also present in thermophilic archaea from different phyla, but Tat-signal sequences are exclusive to pilins of halophilic archaea. Nevertheless, we find that Tat signal peptides in haloarchaeal TafE-like pili were exchanged back to the Sec signal peptides on multiple independent occasions. These findings expand our understanding of the diversity and evolution of archaeal extracellular filaments and highlight the Tat pathway as a route for pilus assembly in halophilic archaea.

  PublisherOA PDFDOI

• Sequence Programmable Order–Disorder Transitions in Supramolecular Assembly of Peptide Nanofibers

  Journal of the American Chemical Society · 2025-07-07 · 3 citations

  articleOpen access

  Protein-protein interactions determine the assembly of complexes that are responsible for numerous key biological processes. The assembly of many natural protein complexes is mediated by post-translational structural changes and environmental stimuli. In this study, we show that incorporation of adjacent lysine residues results in the pH-tunable stability of peptide secondary structure and assembly, allowing for the incorporation of complementary order-inducing motifs. The strategic placement of cysteine pairs in the same peptide sequence results in redox-dependent disulfide staple formation, inducing a transition from random coil to β-sheet conformation and subsequent supramolecular nanofiber assembly from otherwise disordered peptide monomers. Spectroscopic, imaging, molecular dynamics, and kinetic studies highlight the critical role of sequence motif location, oligomerization, and the competitive interplay between intra- and interpeptide disulfide bonding in determining assembly outcomes. We extend this approach to demonstrate phosphorylation-dependent assembly from the design of the same parent peptide sequence, suggesting a general approach to the design of diverse stimulus-responsive peptide sequences for supramolecular assembly. These findings also provide a framework for investigating sequence-dependent pathways in amyloid fiber formation with potential implications for neurodegenerative disease research.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R01GM081303

  NIH · $3.6M · 2019

• NIH Grant R01EB001567

  NIH · $3.6M · 2016

• NIH Grant S10OD018149

  NIH · $500k · 2015

• NIH Grant P41RR002250

  NIH · $9.3M · 2014

• NIH Grant R01GM035269

  NIH · $7.0M · 2018

Frequent coauthors

• Albina Orlova

  University of Virginia

  93 shared

• Xiong Yu

  Guiyang Medical University

  89 shared

• Fengbin Wang

  University of Alabama at Birmingham

  67 shared

• Vitold E. Galkin

  Eastern Virginia Medical School

  65 shared

• Mart Krupovìč

  Institut Pasteur

  53 shared

• Virginija Cvirkaitė‐Krupovič

  Institut Pasteur

  38 shared

• Emil Reisler

  University of California, Los Angeles

  35 shared

• Weili Zheng

  University of Virginia

  29 shared

Education

• Postdoc

  MRC Laboratory of Molecular Biology

  1984

• Ph.D.

  Brandeis University

  1982