Zouhair M. Atassi, Ph.D., D.Sc.
Department of Biochemistry and Molecular Biology
Department of Immunology
Robert A. Welch Chair in Chemistry
Education and Awards
- Ph.D., Chemistry, 1960, University of Birmingham, England
- Postdoctoral, Chemistry, 1960-1962, University of Birmingham, England
- Protein Chemistry, 1962-1963, Division of Laboratories and Research, New York State Health Department, Albany, NY
- D.Sc., Chemistry, 1973, University of Birmingham, England
- Harden Medal, The Biochemical Society, London, 1987
- Citation Award, Medico-Legal Society of Japan, 1988
- The Kuwait Prize, 1995
- The Japanese Society of Electrophoresis Award, 1996
Protein Structure and Function; Molecular and Cellular Immunology
By applying and devising tools of chemistry, we completed mapping and synthesis of the antigenic sites (epitopes) of myoglobin and lysozyme, in 1975 and 1978 respectively. These were the first two proteins for which 3-D structures were known. We have since determined antigenic structures of at least 10 more proteins and mapped T-cell recognition for eight of them. In a series of articles, many of which are citation classics, this laboratory provided first comparisons of T- and B-cell recognition of proteins at a sub-molecular level and demonstrated roles of epitope-specific interactions involving T- and B-cells. We showed that Ab and T-cell responses to each epitope are controlled separately by the host’s Major Histocompatibility Complex (MHC). Our pioneering discovery that small peptides are immunogenic provided a powerful tool in biology and medicine.
We defined and synthesized acetylcholine receptor (AChR) functional sites, including those for acetylcholine, α-neurotoxins, autoAbs and/or T-cells. AChR is involved in postsynaptic neuromuscular transmission. Detrmination of its functional sites provided molecular explanation for myasthenia gravis, an autoimmune disease to AChR. Two or 3 auto-determinants, presented by certain DQ haplotypes, were pathogenic. We manipulated autoimmunity by epitope-specific immune tolerance, by tolerogen-conjugated suppression of pathogenic epitopes or by Abs against peptides mimicking the rim of the epitope-binding region on correlate HLA allele. This afforded tools for manipulating autoimmune responses by selectively targeting the epitope-binding region on a presenting MHC allele(s) without affecting immune functions of other MHC molecules.
We have determined and synthesized the functional regions on human DR2 antigen, a genetic restriction molecule involved in antigen presentation to human T cells, the functional sites of allergens, α-bungarotoxin, and influenza A hemagglutinin. Immunization with synthetic α-bungarotoxin or influenza A virus epitopes protected against correlate agent. Most recently we reported localization of the receptor, and Ab and T cell recognition sites on botulinum neurotoxins types A (see Figure) and B (almost 1300 residues each), the most toxic substances known. The findings elucidated the immune defense against these toxins and provided for rational designs of synthetic anti-toxin vaccines.
These contributions have afforded new tools for clinical, diagnostic and therapeutic applications and are widely used for molecular localization and synthesis of a variety of protein binding sites, and regions of molecular and cellular immune responses. Most notable have been the “synthetic overlapping peptides”, "surface-simulation synthesis" and peptide immunization.
Our findings that immune responses target selected sites on a protein surface were strongly criticized in 1983 because they contradicted a prevailing view that the “entire protein is recognized as a continuum”, but are now taken for granted. Dr. Atassi has received many honors and awards, mong which are the Kuwait Prize in Basic Sciences the Harden Medal and Jubilee Lecture of the Biochemical Society. He has been named Distinguished Lecturer and/or honorary professor by a number of US and foreign universities and institutions.
Dr. Atassi has published over 350 research articles and edited/co-edited 15 books. He is Editor-in-Chief of Protein Journal, Protein Reviews; Critical Reviews in Immunology, Forum on Immunopathological Diseases and Therapeutics; Editorial Committee of Immunological Investigations; Editorial Board member of a number of other journals; member Scientific Advisory Board of the Neurotoxin Institute; Scientific Advisory Board of Center for Bio-security Science, Los Alamos National Laboratory; President of the Institute of Immunobiology and International Symposium of Immunobiology, the King Faisal International Prize selection committees for science and for medicine. Previous positions include: Member of the Edman Award Selection Committee, Chair of International Conference on Methods in Protein Structure Analysis (MPSA 1994), co-chair of International Conference on Neurotoxins (ICON 2006).
Current research focuses primarily on mechanisms and manipulation of autoimmunity and molecular recognition of, and protection against, botulinum neurotoxins.
Right: Surface map of the botulinum neurotoxin, type A (BoNT/A) showing regions that we found to bind strongly with human anti-BoNT/A antibodies. The receptor binding domain has four (C10, C15, C20, and C31) antigenic sites, the L-chain three (L11,L14,andL18), and the translocation domain one (N25). Surface accessible regions are available on both faces of the molecule (images are rotated ∼180◦). Figure from: Atassi, Dolimbek, Jankovic, Steward, Aoki (2011) Immunobiology, in press.
Left: A computer-generated lysozyme model showing the relative positions of the residues constituting the three discontinuous antigenic sites of the protein molecule: dotted lines, site 1; dashed lines, site 2; bold-faced lines, site 3. It should be noted that from this perspective, most of site 2 is on the back side of the molecule and only Trp-62 should be visible. Our laboratory first determined the precise locations of these sites chemically and then we mimicked the sites synthetically by a novel approach we termed "surface-simulation" synthesis.
- Dolimbek BZ, Steward LE, Aoki KR, Atassi MZ. Location of the synaptosome-binding regions on botulinum neurotoxin B. Biochemistry. 2012 Jan 10;51(1):316-28.
- Atassi MZ, Dolimbek BZ, Steward LE, Aoki KR. Antibodies against a synthetic peptide designed to mimic a surface area of the H chain of botulinum neurotoxin A. Immunol Lett. 2012 Feb 29;142(1-2):20-7.
- Atassi MZ, Oshima M, Dolimbek BZ, Aoki KR. Antibody and T cell recognition of the light chain of botulinum neurotoxin A in two high-responder mouse strains. Immunobiology. 2012 Jan;217(1):1-7.
- Atassi MZ, Jankovic J, Steward LE, Aoki KR, Dolimbek BZ. Molecular immune recognition of botulinum neurotoxin B. The light chain regions that bind human blocking antibodies from toxin-treated cervical dystonia patients. Antigenic structure of the entire BoNT/B molecule. Immunobiology. 2012 Jan;217(1):17-27.
- Oshima M, Deitiker PR, Jankovic J, Duane DD, Aoki KR, Atassi MZ. Human T-cell responses to botulinum neurotoxin. Responses in vitro of lymphocytes from patients with cervical dystonia and/or other movement disorders treated with BoNT/A or BoNT/B. J Neuroimmunol. 2011 Dec 15;240-241:121-8.
- Oshima M, Deitiker PR, Smith RG, Mosier D, Atassi MZ. T-cell recognition of acetylcholine receptor provides a reliable means for monitoring autoimmunity to acetylcholine receptor in antibody-negative myasthenia gravis patients. Autoimmunity. 2012 Mar;45(2):153-60.
- Oshima M, Deitiker PR, Jankovic J, Duane DD, Aoki KR, Atassi MZ. Human T-cell responses to botulinum neurotoxin: proliferative responses in vitro of lymphocytes from botulinum neurotoxin A-treated movement disorder patients. J Neuroimmunol. 2011 Aug 15;237(1-2):66-72.
- Atassi MZ, Deitiker PR. Does Clostridium botulinum neurotoxin A exhibit molecular mimicry with thyroid autoantigens and cause thyroid complications in predisposed persons? Endocrine. 2011 Aug;40(1):140-1; author reply 142-3.
- Dolimbek BZ, Aoki KR, Atassi MZ. Reduction of antibody response against botulinum neurotoxin A by synthetic monomethoxypolyethylene glycol-peptide conjugates. Immunol Lett. 2011 Jun 30;137(1-2):46-52. doi: 10.1016/j.imlet.2011.02.002.
- Atassi MZ, Dolimbek BZ, Jankovic J, Steward LE, Aoki KR. Regions of botulinum neurotoxin A light chain recognized by human anti-toxin antibodies from cervical dystonia patients immunoresistant to toxin treatment. The antigenic structure of the active toxin recognized by human antibodies. Immunobiology. 2011 Jul;216(7):782-92.
- Dolimbek BZ, Steward LE, Aoki KR, Atassi MZ. Regions of recognition by blocking antibodies on the light chain of botulinum neurotoxin A: antigenic structure of the entire toxin. Immunobiology. 2011 Jun;216(6):698-706.
- Deitiker PR, Oshima M, Smith RG, Mosier D, Atassi MZ. Association with HLA DQ of early onset myasthenia gravis in Southeast Texas region of the United States. Int J Immunogenet. 2011 Feb;38(1):55-62. doi: 10.1111/j.1744-313X.2010.00979.x.
- Deitiker PR, Oshima M, Jankovic J, Duane DD, Aoki KR, Atassi MZ. Association of HLA Class II alleles and haplotypes with cervical dystonia: HLA DR13-DQ6 (DQB1*0604) homozygotes are at greatly increased risk of cervical dystonia in Caucasian Americans. Autoimmunity. 2011 May;44(3):167-76.
- Atassi MZ, Bonavida B. Clinical Applications of Photodynamic Therapy. Forum on Immunopathological Diseases and Therapeutics, 2(3), 273–276 (2011).
- Bonavida B, Atassi MZ. Molecular and Biochemical Mechanisms of Photodynamic Therapy Anti-Tumor Effects. Forum on Immunopathological Diseases and Therapeutics, 2(3), 277–280 (2011).