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, Sly5 Members and 1 Fellow, National Academy of Inventors
Chang, Di Cera, Heyduk, Lodge, Pozzi, Sverdrup2 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
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Publications
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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
Sequential membrane remodeling by cholesterol distinctly modulates HCN channels in naïve and neuropathic DRG neurons
Sequential membrane remodeling by cholesterol distinctly modulates HCN channels in naïve and neuropathic DRG neurons
Cholesterol, abundantly present in distinct plasma membrane pools, is a critical modulator of ion channel function, including hyperpolarization-activated cyclic nucleotide-gated (HCN) channels that regulate the excitability of dorsal root ganglion (DRG) nociceptor neurons. Depletion of membrane cholesterol potentiated HCN channel opening and accelerated activation kinetics, whereas cholesterol supplementation reduced channel opening and slowed activation kinetics. However, the relative contributions of cholesterol that organizes ordered membrane domains (OMDs) versus freely accessible cholesterol pools to HCN channel modulation remain unknown. Using fluorescence lifetime imaging microscopy, FRET and fluorescence anisotropy techniques, we examined how supplementing cholesterol alters plasma membrane properties and HCN gating in nociceptor DRG neurons. We uncovered a process of sequential, stepwise membrane remodeling: an initial phase with OMD expansion and a rapid rise in free cholesterol, followed by continued accumulation of free cholesterol without further OMD expansion. Notably, the slope factor of the HCN G-V relationship is sensitive to OMD expansion but remains unaffected by changes in free cholesterol. Other gating parameters, including open probability and activation kinetics, were affected by elevating free cholesterol. In a rat model of nerve injury, where DRG neurons exhibit reduced free cholesterol levels and smaller OMDs, HCN channel modulation by cholesterol involves contributions from both OMD expansion and free cholesterol accumulation. In contrast, in naïve DRG neurons-characterized by high cholesterol and large OMDs-modulation occurs mostly via increased free cholesterol. These findings provide mechanistic insights into cholesterol-dependent modulation of ion channels and its role in neuropathic pain.
β-Glycoprotein I: structure, mechanisms of autoantibody recognition, and polymorphisms
β-Glycoprotein I: structure, mechanisms of autoantibody recognition, and polymorphisms
Identified in the 1990s as the primary target of antiphospholipid antibodies (aPL) in antiphospholipid syndrome (APS), β2-glycoprotein I (β2GPI) remains a central focus in hematology and immunology. Anti-β2GPI antibodies are important not only for diagnosing APS but also play a key role in causing thrombosis and pregnancy complications in these patients. Elucidating the molecular basis of antibody-β2GPI interactions is therefore critical for advancing APS research and has broad implications for understanding related thrombotic autoimmune disorders. In this review, we summarize recent progress on the structural biology of β2GPI, discuss mechanisms of autoantibody recognition, and provide an update on genetic polymorphisms. By resolving longstanding controversies and uncovering new regulatory principles, structural insights are paving the way for targeted approaches aimed at selectively neutralizing pathogenic autoantibodies without broadly impairing coagulation or immune function, offering promising paths toward transformative APS therapies.
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.
A quantitative cell-based reporter links TDP-43 aggregation and dysfunction to define pathogenic mechanisms
A quantitative cell-based reporter links TDP-43 aggregation and dysfunction to define pathogenic mechanisms
TDP-43 pathology is a hallmark of fatal neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and limbic-predominant age-related TDP-43-encephalopathy (LATE). In affected patients, cytoplasmic TDP-43 aggregates are accompanied by disruption of its normal nuclear localization and function. Because TDP-43 is an RNA binding protein that controls transcript processing, including repression of cryptic exon splicing, its loss leads to dysregulation of gene expression. Despite its central significance in disease, the connection between TDP-43 aggregation and dysfunction remains poorly understood, and models to study the underlying mechanisms are limited. Here, we characterize a robust and quantitative cell-based reporter that captures both aggregation and the resulting loss of function. Using this human biosensor cell line, we show that aggregation initiated by prion-like seeding drives progressive depletion of nuclear TDP-43 and induces signature features of diminished TDP-43 activity, such as increased DNA damage and activation of cryptic exon splicing. We find that aggregate seeding also induces cryptic exon splicing in human neurons implying that this pathological link extends to disease-relevant models. The seeding model provides a platform for dissecting mechanisms that underlie TDP-43 pathology and for identifying factors that modulate the aggregation-to-dysfunction transition. Our data shows that aggregate seeding impacts TDP-43 autoregulation, initiating a toxic feed-forward mechanism that disrupts TDP-43 homeostasis. Furthermore, reducing ataxin-2 levels decreases aggregation and restores TDP-43 activity. Together, these findings reveal a molecularly guided strategy to directly impact TDP-43 activity by decreasing its misfolding and aggregation, highlighting approaches to prevent TDP-43 dysfunction and mitigate toxicity under pathological conditions.
Delineation of a novel assembly intermediate in Rous sarcoma virus integration pathway
Delineation of a novel assembly intermediate in Rous sarcoma virus integration pathway
Retroviral integration is mediated by viral integrase (IN), which synapses two viral long terminal repeat DNA ends and produces a series of nucleoprotein complexes known as intasomes. While structural studies of mature intasomes have illuminated key aspects of their architecture and provided insights into the integration reaction, the sequence of events driving IN oligomerization and engagement of the viral DNA pairing remains unclear. Here, using complementary biochemical and biophysical approaches, including ensemble and single-molecule Fӧrster resonance energy transfer, we reveal that integration progresses through a key transient intermediate that leads to the mature intasome. We demonstrate that Rous sarcoma virus intasome assembly pathway proceeds through a tetrameric intermediate where two IN dimers engage a single DNA end. This complex subsequently oligomerizes to form mature, functional octameric intasome in which two DNA ends are juxtaposed for concerted integration. These findings provide mechanistic insights into the stepwise pathway of retroviral integration and define a previously uncharacterized intermediate critical for intasome maturation, and possibly a drug target for clinically relevant retroviruses.
In vivo targeting of open prothrombin with the monoclonal antibody POmAb results in anticoagulation without excessive bleeding
In vivo targeting of open prothrombin with the monoclonal antibody POmAb results in anticoagulation without excessive bleeding
Antiphospholipid antibodies targeting prothrombin are frequently found in antiphospholipid syndrome (APS), yet their impact on thrombin generation remains unclear. Prothrombin exists in equilibrium between closed and open conformations, influencing its activation to thrombin. We recently identified Prothrombin Open monoclonal Antibody (POmAb), a monoclonal antibody that binds the open form and reduces thrombin generation in plasma. However, the in vivo effects of POmAb on coagulation remain unknown.
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.
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.
