Alex J. Vecchio
Alex J. Vecchio
Assistant Professor
Department of Structural Biology
Jacobs School of Medicine & Biomedical Sciences
Specialty/Research Focus
Biophysics; Computational Biology; Membrane Biophysics; Membrane Proteins; Molecular Basis of Disease; Protein Engineering; Protein Function and Structure; Protein Therapeutics; Structural Biology; Targeted Drug Delivery; X-ray Crystallography
Professional Summary:
The Vecchio laboratory does basic, interdisciplinary research that employs both classic and state-of-the-art techniques in the fields of structural biology, biochemistry, and biophysics—with the goal of advancing fundamental understanding of and solve problems in human biology and health. The research focus of the lab intends to elucidate the structures and assembly processes of small integral membrane protein-comprised supramolecular machines. Proper structure and assembly of these proteins leads to natural homeostatic physiology, while disruptions or disassembly cause disease. Our research requires an understanding of cell & molecular biology, biotechnology & bioinformatics, and biochemistry & biophysics—as the answers to questions we investigate demand bridging gaps at the physics/chemistry/biology interface.
Current research topics include: (1) 3D structure determination of small integral membrane proteins and their complexes by crystallographic & electron microscopic techniques; (2) Quantitative biochemical and biophysical characterization of membrane protein/protein interactions essential for supramolecular assembly; and (3) Development of biomolecular tools to investigate structure/function relationships between small multi-protein complexes and for enabling determination of their structures by cryogenic electron microscopy.
Education and Training:
- Postdoctoral Scholar and Specialist II, University of California, San Francisco (UCSF), Department of Biochemistry & Biophysics (2018)
- Fellowship, NIH NRSA Postdoctoral Fellow, University of California, San Francisco (UCSF), Department of Biochemistry & Biophysics (2015)
- Postdoctoral Scholar, University at Buffalo, SUNY, Department of Structural Biology (2012)
- PhD, Structural Biology, University at Buffalo, SUNY (2011)
- BS, Biology, Rochester Institute of Technology (2000)
Employment:
- Assistant Professor, Department of Structural Biology, University at Buffalo, SUNY Jacobs School of Medicine and Biomedical Sciences (2023-present)
- Assistant Professor, Department of Biochemistry, University of Nebraska-Lincoln (2018–2023)
- Lecturer, Department of Chemistry and Biochemistry, San Francisco State University (2016)
- Adjunct Professor, Department of Biology, University of San Francisco (2015–2016)
- Scientist, Bristol-Myers Squibb (2001–2006)
Awards and Honors:
- Maximizing Investigators’ Research Award (MIRA), NIH NIGMS (2020)
- Early Stage Investigator, University of Nebraska-Lincoln, Nebraska Center for Integrated Biomolecular Communication (2019)
- Ruth L. Kirschstein National Research Service Award Individual Postdoctoral Fellowship, NIH NIGMS (2012)
- Dean's Award for Outstanding Dissertation Research, University at Buffalo, SUNY School of Medicine and Biomedical Sciences (2012)
Research Expertise:
- Membrane Protein Structure and Function: Claudins, Occludin, Tricellulin, Tight Junctions, Paracellular Transport, Lipid-synthesizing Enzymes, Scaffolding Proteins, Clostridium perfringens Enterotoxin
- Protein Biochemistry and Biophysics: Chromatography, Protein/Protein & Protein/Lipid Interactions, Binding Equilibria, Bio-layer Interferometry, Microscale Thermophoresis
- Structural Biology: X-ray Crystallography, Cryogenic Electron Microscopy (Cryo-EM), Microcrystal Electron Diffraction (MicroED)
UB 2020 Strategic Strengths:
- Health and Wellness Across the Lifespan
- Molecular Recognition in Biological Systems and Bioinformatics
Grants and Sponsored Research:
- August 2020–July 2025
Structure and assembly of membrane proteins at tight junctions
NIH NIGMS
Role: Principal Investigator
$1,802,852 - February 2022–July 2023
RII Track-4:NSF: Structures of Membrane Protein Assemblies Resolved by Cryogenic Electron Microscopy
NSF EPSCoR
Role: Principal Investigator
$219,836 - February 2021–July 2023
Impact of claudin-1 inhibition on chemoresistance and metastasis of colon cancer
NIH NCI
Role: Co-Investigator
$148,500 - January 2019–July 2020
Molecular basis for association and dissociation of tight junctions
NIH NIGMS
Role: Principal Investigator
$300,000
Patents:
- Methods and compositions for delivery to and across the blood brain barrier. Described herein are nanoparticle compositions that can be used to target specific regions of the blood brain barrier (BBB). Such nanoparticle compositions can be used to deliver therapeutics to or across the BBB or to image the BBB or the permeability thereof. (2024)
Journal Articles:
- Pacesa M, Nickel L, Schellhaas C, Schmidt J, Pyatova E, Kissling L, Barendse P, Choudhury J, Kapoor S, Alcaraz-Serna A, Cho Y, Ghamary KH, Vinué L, Yachnin BJ, Wollacott AM, Buckley S, Westphal AH, Lindhoud S, Georgeon S, Goverde CA, Hatzopoulos GN, Gönczy P, Muller YD, Schwank G, Swarts DC, Vecchio AJ, Schneider BL, Ovchinnikov S, Correia BE. (2024) BindCraft: one-shot design of functional protein binders. bioRxiv : the preprint server for biology (Dec) doi:10.1101/2024.09.30.615802
- Ogbu CP, Mandriota AM, Liu X, de Las Alas M, Kapoor S, Choudhury J, Kossiakoff AA, Duffey ME, Vecchio AJ. (2024) Biophysical Basis of Paracellular Barrier Modulation by a Pan-Claudin-Binding Molecule. bioRxiv : the preprint server for biology (Nov) doi:10.1101/2024.11.10.622873
- Rathnayake SS, Erramilli SK, Kossiakoff AA, Vecchio AJ. (2024) Cryo-EM structures of Clostridium perfringens enterotoxin bound to its human receptor, claudin-4. Structure (Sep)S0969-2126(24)00384-8. doi:10.1016/j.str.2024.09.015
- Goverde CA, Pacesa M, Goldbach N, Dornfeld LJ, Balbi PEM, Georgeon S, Rosset S, Kapoor S, Choudhury J, Dauparas J, Schellhaas C, Kozlov S, Baker D, Ovchinnikov S, Vecchio AJ, and Correia BE. (2024) Computational design of soluble and functional membrane protein analogues. Nature (Jul), 8020(631) doi:doi: 10.1038/s41586-024-07601-y
- Rathnayake SS, Erramilli SK, Kossiakoff AA, and Vecchio AJ. (2024) Cryo-EM Structures of Clostridium perfringens Enterotoxin Bound to its Human Receptor, Claudin-4. bioRxiv (Jul)(2024.07.11.603128) doi:doi: https://doi.org/10.1101/2024.07.11.603128
- Erramilli SK, Dominik PK, Ogbu CP, Kossiakoff AA, and Vecchio AJ. (2024) Structural and biophysical insights into targeting of claudin-4 by a synthetic antibody fragment. Commun Biol (Jun), 733(7) doi:https://doi.org/10.1038/s42003-024-06437-6.
- Goverde CA, Pacesa M, Goldbach N, Dornfeld LJ, Balbi PEM, Georgeon S, Rosset S, Kapoor S, Choudhury J, Dauparas J, Schellhaas C, Kozlov S, Baker D, Ovchinnikov S, Vecchio AJ, Correia BE. (2024) Computational design of soluble functional analogues of integral membrane proteins. bioRxiv : the preprint server for biology (Mar) doi:10.1101/2023.05.09.540044
- Primeaux M., Liu X., Gowrikumar S., Fatima I., Fisher K.W., Bastola D., Vecchio A.J., Singh A.B., and Dhawan P. (2023) Claudin-1 interacts with EPHA2 to promote cancer stemness and chemoresistance in colorectal cancer. Cancer Letters (Nov), 579(28): 216479. doi:10.1016/j.canlet.2023.216479
- Ogbu C.P., Kapoor S., Vecchio A.J. (2023) Structural basis of Clostridium perfringens enterotoxin activation and oligomerization by trypsin. Toxins (Basel) (Oct), 15(31): 11. doi:10.3390/toxins15110637
- Erramilli SK, Dominik PK, Ogbu CP, Kossiakoff AA, Vecchio AJ. (2023) Cryo-EM structures of a synthetic antibody against 22 kDa claudin-4 reveal its complex with Clostridium perfringens enterotoxin. bioRxiv : the preprint server for biology (Jun). doi:10.1101/2023.06.12.544689
- Fatima I, Uppada JP, Chhonker YS, Gowrikumar S, Barman S, Roy S, Tolentino KT, Palermo N, Natarajan A, Beauchamp DR, Vecchio A, Murry DJ, Singh AB, Hopkins CR, Dhawan P. (2023) Identification and characterization of a first-generation inhibitor of claudin-1 in colon cancer progression and metastasis. Biomedicine & Pharmacotherapy (Mar), 159: 114255.
- Orlando BJ, Dominik PK, Roy S, Ogbu CP, Erramilli SK, Kossiakoff AA, Vecchio AJ. (2022) Development, structure, and mechanism of synthetic antibodies that target claudin and Clostridium perfringens enterotoxin complexes. The Journal of biological chemistry (Sep), 298(9): 102357. doi:10.1016/j.jbc.2022.102357
- Ogbu CP, Roy S, Vecchio AJ. (2022) Disruption of Claudin-Made Tight Junction Barriers by Clostridium perfringens Enterotoxin: Insights from Structural Biology. Cells (Mar), 11(5). doi:10.3390/cells11050903
- Bony BA, Tarudji AW, Miller HA, Gowrikumar S, Roy S, Curtis ET, Gee CC, Vecchio A, Dhawan P, Kievit FM. (2021) Claudin-1-Targeted Nanoparticles for Delivery to Aging-Induced Alterations in the Blood-Brain Barrier. ACS nano (Nov), 15(11): 18520-18531. doi:10.1021/acsnano.1c08432
- Vecchio AJ, Rathnayake SS, Stroud RM. (2021) Structural basis for Clostridium perfringens enterotoxin targeting of claudins at tight junctions in mammalian gut. Proceedings of the National Academy of Sciences of the United States of America (Apr), 118(15). doi:10.1073/pnas.2024651118
- Li F, Egea PF, Vecchio AJ, Asial I, Gupta M, Paulino J, Bajaj R, Dickinson MS, Ferguson-Miller S, Monk BC, Stroud RM. (2021) Highlighting membrane protein structure and function: A celebration of the Protein Data Bank. The Journal of biological chemistry (Jan), 296: 100557. doi:10.1016/j.jbc.2021.100557
- Vecchio AJ, Stroud RM. (2019) Claudin-9 structures reveal mechanism for toxin-induced gut barrier breakdown. Proceedings of the National Academy of Sciences of the United States of America (Sep), 116(36): 17817-17824. doi:10.1073/pnas.1908929116
- Vecchio AJ, Stroud RM. (2019) High-Throughput Nano-Scale Characterization of Membrane Proteins Using Fluorescence-Detection Size-Exclusion Chromatography. Methods in molecular biology (Clifton, N.J.) (Jan), 2025: 361-388. doi:10.1007/978-1-4939-9624-7_17
- Lucido MJ, Orlando BJ, Vecchio AJ, Malkowski MG. (2016) Crystal Structure of Aspirin-Acetylated Human Cyclooxygenase-2: Insight into the Formation of Products with Reversed Stereochemistry. Biochemistry (Mar), 55(8): 1226-38. doi:10.1021/acs.biochem.5b01378
- Vecchio AJ, Orlando BJ, Nandagiri R, Malkowski MG. (2012) Investigating substrate promiscuity in cyclooxygenase-2: the role of Arg-120 and residues lining the hydrophobic groove. The Journal of biological chemistry (Jul), 287(29): 24619-30. doi:10.1074/jbc.M112.372243
- Vecchio AJ, Malkowski MG. (2011) The structure of NS-398 bound to cyclooxygenase-2. Journal of structural biology (Nov), 176(2): 254-8. doi:10.1016/j.jsb.2011.07.019
- Vecchio AJ, Malkowski MG. (2011) The structural basis of endocannabinoid oxygenation by cyclooxygenase-2. The Journal of biological chemistry (Jun), 286(23): 20736-45. doi:10.1074/jbc.M111.230367
- Dong L, Vecchio AJ, Sharma NP, Jurban BJ, Malkowski MG, Smith WL. (2011) Human cyclooxygenase-2 is a sequence homodimer that functions as a conformational heterodimer. The Journal of biological chemistry (May), 286(21): 19035-46. doi:10.1074/jbc.M111.231969
- Vecchio AJ, Simmons DM, Malkowski MG. (2010) Structural basis of fatty acid substrate binding to cyclooxygenase-2. The Journal of biological chemistry (Jul), 285(29): 22152-63. doi:10.1074/jbc.M110.119867
Abstracts:
- (2023) A Brief Intro to Research in the Vecchio Laboratory. Annual Buffalo-Hamilton-Toronto (BHT) Crystallography-CryoEM Symposium. Hamilton, ON, Canada (Nov) Oral
- (2023) A Platform to Resolve Structure of Claudins by Cryo-EM. Tight Junctions: From Structure and Development to Therapeutics Conference. Leysin, Switzerland (Jun) Oral
- (2022) Cryo-EM Structures of Human Claudin-4 in Complex with its Bacterial Toxin Antagonist Enabled by Synthetic Antibody Fragments Reveal Targeting Mechanisms and Therapeutic Potential. Biophysical Society 66th Annual Meeting. San Francisco, CaliforniaUnited States (Feb) Oral
- (2021) Molecular and Structural Basis Underlying Selective Targeting of Claudins by Clostridium perfringens Enterotoxin in Mammalian Gut. ASBMB Annual Meeting, Experimental Biology 2021. (Apr) Oral
Professional Memberships:
- ASBMB
- Biophysical Society
- Protein Society
Presentations:
- "Cryo-EM and Fiducial Marks as Fail-safes for Structural Studies of Very Small Membrane Proteins" NIH Common Fund Transformative High Resolution Cryo-EM Program Service Centers Current Practices Webinar (2024)
- "Structural basis of Clostridium perfringens enterotoxin activation and oligomerization by trypsin" Biophysical Society Annual Meeting (2024)
- "Structure and Mechanism of a Claudin-Binding Antibody Fragment for Modulating Tight Junction Permeability" University at Buffalo Department of Biochemistry Seminar Series (2023)
- "A Platform to Resolve Structure of Claudins by Cryo-EM" Buffalo Protein Science Group Seminar Series (2023)
- "Natural and synthetic molecules that enable structure determination of claudins reveal mechanisms of and strategies to treat Clostridium perfringens enterotoxin-based gastrointestinal disorders" 65th Canadian Society for Molecular Biosciences Meeting: Membrane Proteins in Health and Disease; Banff, Alberta, Canada (2022)
- "Structural and biophysical basis of Clostridium perfringens enterotoxin recognition of mammalian claudins" ACS Midwest Regional Meeting (2021)
- "Structural basis for Clostridium perfringens enterotoxin breakdown of claudin-made barriers in mammalian gut" Department of Biochemistry & Molecular Biophysics Seminar Series, Kansas State University (2021)
- "Structural basis of human claudin-9 ion selectivity and dissociation of tight junctions by a bacterial toxin" UNMC Veterans Affairs Seminar Series (2019)
Service Activities:
- Seminar Committee, Department of Structural Biology; Co-Chair (2024–present)
- TT Faculty Search Committee Department of Structural Biology; Member (2023–2024)
- PPBS Graduate Admissions Committee; Member (2023–2024)
- Jacobs School Faculty Council; Member (2023–present)
- Pacific Northwest Center for Cryo-EM (PNCC); External Proposal Reviewer (2023–present)
- Comprehensive Research Data Strategy Task Force; University of Nebraska-Lincoln (2023)
- Graduate Recruitment and Admissions Committee, University of Nebraska-Lincoln, Department of Biochemistry; Member (2022–2023)
- Protein Assemblies, Biophysical Society 66th Annual Meeting; Platform Co-Chair (2022)
- Faculty Advisory Committee at the University of Nebraska-Lincoln, College of Agricultural Sciences and Natural Resources; Member (2021–2023)
- Web IT Committee, University of Nebraska-Lincoln, Department of Biochemistry; Chair (2021–2023)
- Immunology Search Committee, University of Nebraska-Lincoln, Department of Biochemistry; Member (2021–2022)
- Cryo-EM Search Committee, University of Nebraska-Lincoln, Department of Biochemistry; Member (2021–2022)
- Structural Biology and Molecular Biophysics, eLife (Journal); Early-Career Reviewer, (2021–present)
- For the following journals, Nature, Nature Communications, eLife, Journal of Cell Biology, Journal of Molecular Biology, Biochimica et Biophysica Acta (BBA); Ad hoc Reviewer (2021–present)
- Patrick Kwabena Oduro, PhD Student UB Structural Biology Mark Primeaux, PhD Student UNMC Biochemistry and Molecular Biology Cole Dolemore, PhD Student UNL Biochemistry Madhuka Liyanage, PhD Student UNL Chemistry; PhD Advisory Committee Member (2020–present)
- Seminar Committee, University of Nebraska-Lincoln, Department of Biochemistry; Chair (2019–2022)
- Undergraduate Curriculum Committee, University of Nebraska-Lincoln, Department of Biochemistry; Member (2019–2022)