EDWARD A. DOISY
Department of
Biochemistry & Molecular Biology
EST. 1924
Saint Louis University School of Medicine
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Our Legacy
1 Nobel Laureate
Doisy2 Members, National Academy of Sciences
Doisy, Sly1 Member, National Academy of Medicine
Roth3 Members, American Academy of Arts & Sciences
Doisy, Roth, Shilatifard1 Member, Leopoldina
Kutchan11 Fellows, American Association for the Advancement of Science
Di Cera, Doisy, Elliott, Katzman, Kutchan, Lee, Lodge, McKee, Olson, Shilatifard, Sly4 Members and 1 Fellow, National Academy of Inventors
Chang, Di Cera, Heyduk, Lodge, Pozzi2 Pew Scholars
Cole, Yap
Message from the Chair
Welcome to our website!
Our department was founded in 1924 by Dr. Edward A. Doisy, discoverer of estrogens and recipient of the 1943 Nobel Prize in Physiology or Medicine for his work on the synthesis of vitamin K.
We have an impressive legacy of excellence, continued by Doisy’s successors Dr. Robert Olson and Dr. William Sly, and by the work of our current outstanding students, postdocs, staff and faculty.
It is an exciting time to join the BMB family.
Thank you for visiting!
Department Stats
External Grant Expenditures
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Registration now open!
2nd Doisy Conference on Coagulation
A one-day, free event for students, trainees, and researchers in the biomedical sciences.
Monday, May 4, 2026
Bayer Event Center, MO Botanical Garden
What's News
Congratulations to Lucas Handlin, Graduate Student in the Dai Lab, for winning 1st place in…
Congratulations to Michelle Brennan, Ph.D., Director of the Genomics and Bioinformatics Core, on being approved…
Congratulations to Lilian Silva, Ph.D., Postdoctoral Fellow in the lab of Susana Gonzalo, on being…
Congratulations to two members of the Antony Lab, Rajnandani Kashyap, Ph.D., Postdoctoral Fellow, and Ayush…
Congratulations to the Dastvan Lab on the installation of their new High Q FATHOM High-Throughput…
Department Committees
Doisy Fund
- Yuna Ayala, Ph.D.
- Ángel Baldán, Ph.D.
- Enrico Di Cera, M.D., Chair
- Kathleen E. Doisy, M.S.
- Oleg Kisselev, Ph.D.
- Krista Lentine, M.D., Ph.D.
- LaChina McCoy
- Eleonore Stump, Ph.D.
Instrumentation and Cores
- Edwin Antony, Ph.D.
- Yuna Ayala, Ph.D.
- Ángel Baldán, Ph.D.
- Michelle Brennan, Ph.D., Chair
- Reza Dastvan, Ph.D.
- Nicola Pozzi, Ph.D.
Training
- Madison Adolph, Ph.D., Co-Director of the BMB Graduate Program
- Yuna Ayala, Ph.D., Chair
- Susana Gonzalo, Ph.D.
- Tomasz Heyduk, Ph.D., Co-Director of the BMB Graduate Program
- LaChina McCoy
BMB Faculty Incentives
SLU Incentives
- F&A Rebate: Percentage of F&A rebated to 2-fund
- Non-salary incentive: Half of salary recovered beyond 50% rebated to 2-fund
- Salary bonus from the faculty compensation plan for faculty who have recovered 50% or more of their total compensation from extramural sources as a 3-year rolling average from preceding FYs
Primary BMB Faculty
- Matching of the SLU F&A rebate
- Cash award for faculty with salary recovery from extramural sources of at least 50% (Assistant Professor), 65% (Associate Professor), or 75% (Professor). Salary recovery in excess of these levels will be rebated to a 2- fund for research use
- Cash award for any grant, new or renewal, with BMB faculty as the PI, generating full indirect costs, and providing at least 4 years of funding
- Cash award of $3,000 for new publications with BMB faculty as the corresponding author in journals with an impact factor greater than 10. Cash award of $2,000 for the leading author of the publication, if a member of BMB
- Full support of the stipend of Ph.D. and M.D./Ph.D. students for 12 months from the date they pass their qualifying exam
Primary & Secondary BMB Faculty
- Matching of JIT grants from the ICTS
- Student support through the Doisy Scholar Program
Dean Loeb Prize
- Cash award of $3,000
Click to read more about the Hanau Loeb Prize.
Doisy Scholar Program
Doisy Scholars
Biochemistry Ph.D. and M.D./Ph.D. students may be appointed as Doisy Scholars at any time after passing their qualifying exams.
- Appointment to Doisy Scholar is recommended by the BMB Training Committee and reviewed for approval by the Chair of BMB.
- Doisy Scholarship is an honor reserved for students who have distinguished themselves academically through course work and have achieved scholarly recognition through peer-reviewed publications and poster/oral presentations at meetings or extramural fellowships.
- The stipend and student fees of a Doisy Scholar are supported in full by the BMB Doisy Fund for 24 months.
- The Doisy Scholar will also receive a cash award each year from the BMB Doisy Fund.
Click to read more about our Doisy Scholars.
High Impact Publications
Papers highlighted below were published in journals with an impact factor of 10 or greater.
All papers were published within the past year.
All papers were published within the past year.
Recent Publications
Mechanisms of DNMT3A-3L-mediated de novo DNA methylation on chromatin
Mechanisms of DNMT3A-3L-mediated de novo DNA methylation on chromatin
De novo DNA methylation is mediated by DNA methyltransferases DNMT3A and DNMT3B, in cooperation with the catalytically inactive paralogs DNMT3L and DNMT3B3. DNMT3L is predominantly expressed in embryonic stem cells to establish methylation patterns and is silenced upon differentiation, with DNMT3B3 substituting in somatic cells. Here we present high-resolution cryo-electron microscopy structures of nucleosome-bound, full-length DNMT3A2-3L and its oligomeric assemblies in the nucleosome-free state. We identified the critical role of DNMT3L as a histone modification sensor, guiding chromatin engagement through a mechanism distinct from DNMT3B3. The structures show a 180° rotated 'switching helix' in DNMT3L that prevents direct interaction with the nucleosome acidic patch. Instead, nucleosome binding is mediated by the DNMT3L ADD domain, while the DNMT3A PWWP domain exhibits reduced engagement in the absence of H3K36 methylation. The oligomeric arrangement of DNMT3A2-3L in nucleosome-free states highlights its dynamic assembly and potential allosteric regulation. We further capture dynamic structural movements of DNMT3A2-3L on nucleosomes. These findings uncover a previously unknown mechanism by which DNMT3A-3L mediates de novo DNA methylation on chromatin through complex assembly, histone tail sensing, dynamic DNA search and regulated nucleosome engagement, providing insights into epigenetic regulation.
PCNA encircling primer/template junctions is eliminated by exchange of RPA for Rad51: implications for the interplay between human DNA damage tolerance pathways
PCNA encircling primer/template junctions is eliminated by exchange of RPA for Rad51: implications for the interplay between human DNA damage tolerance pathways
The DNA genome is constantly exposed to agents, such as ultraviolet radiation (UVR), that can alter or eliminate its coding properties through covalent modifications of the template bases. Many of these damaging modifications (i.e. lesions) persist into the S-phase of the cell cycle, where they may stall the canonical DNA replication machinery. In humans, these stalling events are circumvented by one of at least three interconnected DNA damage tolerance (DDT) pathways: translesion DNA synthesis (TLS), Template Switching (TS), and Homology-dependent Recombination (HDR). Currently, the functional interplay between these pathways is unclear, leaving wide gaps in our fundamental understanding of human DDT. To gain insights, we focus on the activation mechanisms of the DDT pathways. PCNA sliding clamps encircling primer/template junctions of stalled replication sites are central to the activation of both TLS and TS, whereas exchange of RPA for Rad51 filaments on the single-strand DNA (ssDNA) sequences of stalled replication sites is central to HDR activation. Utilizing direct, ensemble FRET approaches developed by our lab, we independently monitor and directly compare PCNA occupancy and RPA/Rad51 exchange at primer/template junctions under a variety of conditions that mimic in vivo scenarios. Collectively, the results reveal that assembly of stable Rad51 filaments at primer/template junctions via RPA/Rad51 exchange causes complete and irreversible unloading of the resident PCNA, both in the presence and absence of an abundant PCNA-binding protein complex. Further investigations decipher the mechanism of RPA/Rad51 exchange-dependent unloading of PCNA. Collectively, these studies provide critical insights into the interplay between human DDT pathways and direction for future studies.
Molecular determinants of allosteric modulation of protein disulfide isomerase by small-molecule b'-ligands
Molecular determinants of allosteric modulation of protein disulfide isomerase by small-molecule b'-ligands
Allosteric modulation is central to enzyme function and an attractive strategy for drug development. Protein Disulfide Isomerase (PDI), the prototypical thiol-isomerase, exemplifies this potential through its structural flexibility and involvement in neurodegeneration, cancer, and thromboinflammatory disorders such as sepsis, stroke, cancer-associated thrombosis, and antiphospholipid syndrome. PDI consists of four thioredoxin-like domains (a-b-b'-a'), with catalytic CGHC motifs in a and a' domains and a ligand-binding pocket in the b' domain. We previously reported that the b'-ligand bepristat 2a (Bep2a) inhibits PDI activity toward large macromolecular substrates while allosterically enhancing activity toward smaller physiological substrates such as GSSG and l-cystine. Here, we define the molecular, thermodynamic, and structural basis of this dual function. Bep2a features an indole ring with five substituents (R1-R5). Using mutagenesis and HDX-MS, we mapped the complex topology, identified five residues (F249, H256, I301, F304, I318) involved in binding, and uncovered a ligand-induced rearrangement of the left helix that acts as a dynamic gate controlling pocket accessibility, a previously unrecognized regulatory mechanism. AI-informed modeling, SAR analysis, and smFRET revealed that Bep2a's indole core binds perpendicularly in the pocket, with the R1 hydroxyl forming a critical hydrogen bond with H256, which is essential for binding but not for allosteric activation. Conversely, the R4 amine projects outward, serving as a key allosteric site that engages the catalytic domains and promotes PDI compaction. These findings uncover fundamental principles of PDI allosteric regulation and provide a blueprint for optimizing existing ligands and designing new ones with defined functional outcomes.
Sterile inflammation in laminopathies
Sterile inflammation in laminopathies
Sterile inflammation, an immune response triggered in the absence of pathogens, plays a key role in various chronic diseases, including aging-related disorders, cancer, and autoimmune conditions. This process is driven by damage-associated molecular patterns, such as self-DNA in the cytosol, which activate innate immune pathways and contribute to persistent inflammation. Chronic activation of these pathways exacerbates tissue damage and accelerates disease progression. Recent studies have connected sterile inflammation to laminopathies, a group of genetic disorders caused by mutations in the LMNA gene, which encodes nuclear intermediate filament proteins essential for nuclear structure and function. In this review we discuss the molecular mechanisms underlying sterile inflammation in laminopathies, emphasizing self-DNA sensing, inflammatory signaling cascade activation, and their pathological consequences. Additionally, we explore potential therapeutic strategies aimed at modulating inflammation and improving disease outcomes. Understanding these interactions may provide new avenues for targeting inflammation in laminopathies and related conditions.
Domain and residue mapping of autoantibodies to β2GPI reveals differences among antiphospholipid syndrome phenotypes
Domain and residue mapping of autoantibodies to β2GPI reveals differences among antiphospholipid syndrome phenotypes
Antiphospholipid antibodies targeting β2-glycoprotein I (β2GPI) are a hallmark of antiphospholipid syndrome (APS), associated with an increased risk of thrombosis and pregnancy morbidity. Among these, antibodies targeting domain I (DI) are common in individuals at higher risk; however, their epitopes and prevalence among APS phenotypes remain unclear. Here, we use a large collection of 29 structurally and functionally validated β2GPI variants to provide new insights into the molecular mechanisms of autoantibody recognition in APS. Using the prototypic human-derived monoclonal anti-DI antibody MBB2, we identified positively charged residue R39 as the key driver of MBB2 binding, followed by residues R43, N56, and T57. Structural analyses revealed that although R39 is solvent exposed, R43 is not, because it is caged by residues N56 and T57. The narrow epitope footprint explains why MBB2 exhibits a modest affinity for soluble β2GPI. The cage structure accounts for the epitope being conformational rather than linear. Mutational analyses of immunoglobulin G anti-β2GPI antibodies from 52 patients with triple-positive APS, 37 with a history of thrombosis and 15 nonvascular obstetric patients, confirmed significant reactivity against DI and showed signatures of 2 conformational epitopes: one similar to MBB2 (epitope I), in which the presence of R39 is essential, and another that does not require R39 (epitope II). Although less frequent than epitope II in our cohort, epitope I reactivity was notably enriched in patients with vascular-obstetric APS. Varying epitope specificities for DI may therefore aid in identifying different APS phenotypes and predicting clinical outcomes.
Mechanism of RPA phosphocode priming and tuning by CDK1/WEE1 signaling circuit
Mechanism of RPA phosphocode priming and tuning by CDK1/WEE1 signaling circuit
Replication protein A (RPA) is a heterotrimeric single-strand DNA binding protein essential for DNA metabolism. Segregation of RPA functions in response to DNA damage is fine-tuned by hyperphosphorylation of the RPA32 subunit that is dependent on cyclin-dependent kinase (CDK)-mediated priming phosphorylation at the Ser-23 and Ser-29 sites. However, the mechanism of priming-driven hyperphosphorylation of RPA and the modulation of cell cycle progression by the RPA-CDK axis remains unresolved. Here, we uncover that the RPA70 subunit is also phosphorylated by CDK1 at Thr-191. This modification is crucial for G2 to M phase transition. This function is enacted through reciprocal regulation of CDK1 activity via a feedback circuit espoused by stabilization of WEE1 kinase. The Thr-191 phosphosite on RPA70 is also crucial for priming hyperphosphorylation of RPA32 in response to DNA damage. Structurally, phosphorylation by CDK1 primes RPA by reconfiguring the domains to release the N-terminus of RPA32 and the two protein-interaction domains. These configurational changes markedly enhance the efficiency of multisite phosphorylation by other kinases independent of RPA-ssDNA interactions. Our findings establish a unique phosphocode-dependent feedback mechanism between RPA and RPA-regulating kinases that is fine-tuned to enact distinct bipartite functions in cell cycle progression and DNA damage response.
Structural details of helix-mediated multimerization of the conserved region of TDP-43 C-terminal domain
Structural details of helix-mediated multimerization of the conserved region of TDP-43 C-terminal domain
Pathological inclusions of the C-terminal domain (CTD) of TAR DNA binding protein-43 (TDP-43) are neurodegenerative hallmarks in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, yet CTD's aggregation propensity complicates structural characterization of native TDP-43. Here we propose structural models for the physiological multimerization of TDP-43 CTD's conserved region (CR) essential for TDP-43 RNA processing. Using NMR spectroscopy, we establish that the native state of TDP-43 CR at physiological conditions is α-helical. Hydrophobic residues drive CR helix-helix assembly, phase separation, and TDP-43 nuclear retention, while polar residues down regulate these processes. An integrative approach combining analytical ultracentrifugation, NMR-derived contacts, AlphaFold2-Multimer modeling, and all-atom molecular dynamics simulations together suggest that TDP-43 CR forms dynamic, multimeric helical assemblies stabilized by a methionine-rich core with specific contributions from a tryptophan/leucine pair. These structures show how ALS-associated mutations disrupt TDP-43 function and provide pharmacologically targetable structures to prevent its conversion into pathogenic β-sheet aggregates.
Recent advances in quantifying protein conformational ensembles with dipolar EPR spectroscopy
Recent advances in quantifying protein conformational ensembles with dipolar EPR spectroscopy
This perspective highlights recent applications and technological progress in dipolar electron paramagnetic resonance (EPR) spectroscopy, including double electron-electron resonance (DEER) spectroscopy. These methods provide nanoscale distance distributions between site-specific spin labels in biomacromolecules. The resulting data are particularly well suited for quantifying the structure and energetics of conformational ensembles of multi-state and flexible proteins. Recent applications span a wide range of systems and are accompanied by innovations in spin labeling, deuteration, in-cell measurements, integrative multi-technique approaches, and novel computational modeling methods combined with structure prediction tools.
2-chlorofatty acid modification of neutrophil proteins: identification, localization and role in NETosis
2-chlorofatty acid modification of neutrophil proteins: identification, localization and role in NETosis
We previously demonstrated neutrophil MPO derived HOCl targets the vinyl ether bond of plasmalogens resulting in the Liberation of 2-chlorofatty aldehydes (2-ClFALDs) and their oxidation products, 2-chlorofatty acids (2-ClFAs), which elicit neutrophil extracellular trap (NET) formation. In this study, the click chemistry analog of 2-chlorohexadecanoic acid (2-ClHA) was utilized to identify 127 proteins covalently modified by 2-ClHA in human neutrophils. Bioinformatics revealed that multiple proteins modified by 2-ClHA are related to protein modification and binding as well as metabolite interconversion. Three key proteins involved in NET formation and function were modified by 2-ClHA including peptidyl arginine deiminase 4 (PAD4), neutrophil defensin alpha 3 (DEFA3), and neutrophil collagenase (MMP8). PAD4 activity was shown to be increased by 2-ClFA treatment. Further studies investigated 2-ClFA modified protein localization over time during NET formation. Initially PAD4 and 2-ClFA-modified proteins were extranuclear but over time they both localized to distinct nuclear regions. Following DNA release from neutrophils, 2-ClFA-modified proteins were found throughout the neutrophil and DNA strands. In summary, multiple neutrophil proteins are modified by 2-ClHA, including PAD4. 2-ClHA modification and activation of PAD4 is suggested as a key component of 2-ClHA elicited NET formation.
Plasminogen mutation-associated thrombotic microangiopathy and role of anticoagulation: a single institution case series
Plasminogen mutation-associated thrombotic microangiopathy and role of anticoagulation: a single institution case series
Knowledge gaps exist regarding the role of coagulation pathway mutations such as those in the plasminogen () gene in the pathogenesis of thrombotic microangiopathy (TMA) and treatment outcomes.
