John D. Lambris, Ph.D.

Description of Research Expertise

Research Interests

Structure, functions, and evolution of complement proteins and viral molecular mimicry.

Research Summary

The complement system, the first line of immunological defense against foreign pathogens, is a very old defense mechanism that emerged at least 600-700 million years ago and predates by far the appearance of the immunoglobulins. Our laboratory focuses on the following aspects of the complement system.

Mapping of C3 regions involved in the C3-ligand interactions.
The elucidation of the molecular features related to the functions of C3 requires the structural analysis of C3-ligand interactions and this has been the focus of our research. By studying the molecule at the protein as well as DNA level, we have successfully identified the binding sites on C3 for properdin, bovine conglutinin, factor H, CR1 (CD35), CR2 (CD21), and C5. The objective of our present projects are to further characterize the subdomains involved in the C3 functions and to evaluate the physicochemical basis for their binding properties.

Complement system and viral molecular mimicry.
The complement system serves as both an innate and an acquired defense against viral infection. In general, activation of the C' system in the presence or absence of antibodies leads to virus neutralization. To circumvent these defenses, viruses not only have developed mechanisms to control C' but have also turned these interactions to their own advantage. Important examples are HIV, herpesvirus, vaccinia virus, and Epstein-Barr virus. Investigations in our laboratory focus on the mechanism of C' inactivation and structural and functional analysis of viral proteins involved in C' evasion.

Complement evolution and diversity.
A comprehensive understanding of any complex biological system such as the C' system, requires a thorough knowledge of its origin, evolution, development, and diversity. For this reason our laboratory has been engaged in the study of the evolution of the C' system for the last 12 years. We have cloned and purified C3 from several animal species and studied their biochemical and functional properties. Recently we have been able to identify and characterize multiple C3 isoforms in fish. It is important to note that in all other species analyzed to date, the functionally active form of C3 exists as the product of a single gene. We hypothesize that fish have developed a unique approach to expand their innate immunity by duplicating their C3 genes. Our long-term goals are to study the origin, development, and structural and functional diversity of the complement system at the molecular level.

Identification of complement inhibitors.
Although the C' system is an important line of defense against pathogenic organisms, its unregulated activation may lead to host cell damage. C' has been implicated in several disease states including but not limited to autoimmune diseases, adult respiratory distress syndrome, cardiopulmonary bypass, xenotransplantation, stroke, heart attack and burn injuries. To date there are no inhibitors of C' activation available in the clinic. Our laboratory has used a random peptide library-based search strategy for the identification of C3-interactive peptides and has discovered a peptide that binds C3 and prevents the activation of complement by both the classical and alternative pathways. This complement inhibiting peptide, named Compstatin, is a disulfided-bonded cyclic peptide of
1551 Da. The peptide is active in vitro and ex vivo models and has properties that suggest clinical potential. The 2D NMR (see figure) and analog data indicate that the type 1 b-turn segment of the peptide forms the C3 binding site. Studies are underway to define the structure- function relationship and design of peptidomimetic drugs.

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Last updated: 09/08/2008
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