Biochemistry Computer Lab Web Site MCDB 108AL Professor Duane W. Sears Professor of Immunology and Biochemistry Department of Molecular, Cellular, and Developmental Biology University of California Santa Barbara

BIOGRAPHICAL SKETCH	Human IgG1
		Lymphotoxin-a

Professor Sears joined the faculty at the University of California Santa Barbara in 1977 following completion of his postdoctoral studies on the biochemistry of murine MHC antigens at Albert Einstein College of Medicine. Prior to that, he earned his Ph.D. in Biophysical Chemistry at Columbia University, analyzing the kinetics of immunoglobulin heavy and light chain assembly, a project which sparked his interest in immunology. His work and teaching at UCSB are both underscored by a fundamental desire to understand the structure-function relationships of proteins, as reflected in the Kuby web site and the instructional web sites created for his courses. The unifying theme of his research at UCSB has been the analysis of immunological cell-killing mechanisms.

• Early studies in Dr. Sears' laboratory aimed at elucidating the structure-function relationships of mutant MHC class I molecules in order to probe the recognition of antigen by cytotoxic T lymphocytes (CTLs) and target cell lysis (1).
• Subsequent studies aimed at elucidating the structure-function relationships of IgG antibody Fcg receptors (FcgRs) expressed on natural killer (NK) lymphocytes in order to probe the killing mechanism of antibody-dependent cell-mediated cytotoxicity(ADCC) (2).
• These studies led to the cloning and characterization of cDNA molecules encoding a family of rat NK FcgRIIImolecules (3) and the murine macrophagehigh affinity FcgRImolecule (4).
• Current studies focus on the creation of novel composite molecules with potential immunotherapeutic and diagnostic properties. In one composite, a portion of the high affinity FcgRI is fused to the antibody Fc itself creating an FcgRI-Fc "receptorbody." These molecules provide a new type of tool for investigating the FcgRI-antibody interaction. At present the precise nature of this interaction can only be inferred since the three-dimensional structure of the FcgRI molecule has not yet been determined. However, the antibody hinge (H) and C_H2 regions are known to be at the focal point of this interaction as illustrated on the web page linked to the image below.

[animated GIF] [312 x 239 pixels; 62898 bytes]

Binding site on human IgG1 for FcgRI.

• In another type of composite, a portion of the high affinity FcgRI is fused to certain members of the tumor necrosis factor (TNF) cytokine family that are known to trigger programmed cell death, or "apoptosis," of certain cell types. The ultimate goal with these "receptorkines" is to target specific cells for killing via the FcgRI. These studies are guided by known features of the interaction between lymphotoxin-a(LT-a, or TNF-b) and TNF-Receptor 1 (TNF-R1; p55), as illustrated on the web page linked to the image below.

Lymphotoxin-a (LT-a) (or TNF-b, center) + 1, 2, and/or 3 TNF-R1chains (outside) See two animated views of this complex [Green residues are membrane proximal.]

1tnr.pdb

Duane W. Sears
Professor of Immunology and Biochemistry
Department of Molecular, Cellular, & Developmental Biology
Interdepartmental Program in Biochemistry and Molecular Biology
University of California Santa Barbara
Santa Barbara, CA 93106

Footnotes:

1. S. S. Burnside, P. Hunt, K. Ozato, and D. W. Sears. "A Molecular Hybrid of the H-2D^d and H-2L^d Genes Expressed in the dm1 Mutant." Proc. Natl. Acad. Sci. USA 81:5204 (1984).
2. J. E. Christiaansen and D. W. Sears. "Unusually Efficient Tumor Cell Lysis by Human Effectors of Antibody-Dependent Cellular Cytotoxicity Mediated by Monoclonal Antibodies." Cancer Res. 44:3712 (1984).
3. D. L. Farber, R. Giorda, M. Y. Nettleton, M. Trucco, J. P. Kochan, and D. W. Sears. "Rat Class III Fcg Receptor Isoforms Differ in IgG Subclass-Binding Specificity and Fail to Associate Productively with Rat CD3z." J. Immunol. 150:4364 (1993).
4. D. W. Sears, N. Osman, B. Tate, I. F. C. McKenzie, and P. M. Hogarth. "Molecular Cloning and Expression of the Mouse High Affinity Fc Receptor for IgG." J. Immunol.144::371 (1990).

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©	Duane W. Sears September 25, 1998