Structural Immunology

Faculty active in this area of research are listed below. For a brief description of their research interests, click on their name in the list. Clicking on the name at the beginning of the brief description links to their detailed personal website.

J. Edwin Blalock, PhD, Department of Medicine
Narayana Venkata Lakshmi Sthanam, PhD., Department of Optometry
Mark R. Walter, PhD, Department of Microbiology

J. Edwin Blalock, PhDThe overall objective of our current research is to delineate certain genetic rules that govern the shape and function of proteins and peptides. Specifically, nucleic acids encode amino acid sequences in a binary fashion with regard to hydropathy. We and others have provided compelling evidence that the exact pattern of polar and nonpolar amino acids, rather than the precise identity of particular R groups, is an important driving for protein shape. Structural proof for this idea is being pursued through determination of the 3-dimensional structures of peptides with dissimilar primary amino acid sequences but identical binary codes. These design principles are being used: 1) to make synthetic peptides specifically targeted to act as agonists and antagonists of Ca++ channels involved in human immunodeficiency virus-mediated apoptosis and 2) to make synthetic peptide vaccines as immunotherapeutic agents against autoimmune diseases of the nervous system such as myasthenia gravis (MG) and multiple sclerosis (MS). Additional research areas include: First, together with colleagues at the University of Utrecht, we are evaluating the aforementioned peptide regulators of Ca++ channels for utility in models of asthma. Second, together with Dick Marchase's group, we are elucidating the structure and function of a novel Ca++ influx factor (CIF) which is a key signal for store-operated Ca++ entry. Third, we are studying the role of these CIF-operated channels, as well as their regulation by glucosamine in diabetes.

Narayana Sthanam, PhD Narayana’s Structural Biology Lab is focused toward understanding the activation, function and regulation of human complement, the innate immune component at the molecular level. With the help of X-ray crystallography and other biophysical techniques, first we initiated structural studies on enzymes that are responsible for the activation of complement. Factor D, factor B and C2 enzymes were investigated and based on our structural work, in combination with mutagenesis and enzyme kinetics, we established ‘substrate induced catalysis’, a new paradigm, as the method of choice used in the activation of the complement in both, classical as well as alternative pathways . We have also initiated structural probing of co-factors C3b, C4b and the structural and functional analogue of the former, the Cobra Venom Factor (CVF), to understand their role in the assembly and function of the critical complement enzymes C3-convertases (C3bBb, C4bC2a and CVFBb). The structural work in combination with enzyme kinetic studies would help us understand the role of C3-convertases ‘driven by conformational changes’ in the complement function. We are focusing our efforts toward understanding the assembly of C3-convertases by probing the interactions between co-factors (C3b, CVF, and C4b) and the catalytic components (Bb and C2a). Because of the potential for causing host tissue damage, all three complement pathways are stringently regulated at each step. A fine balance between the assembly and disassembly of C3- and C5-convertases is essential for the successful regulation of complement. Hence, we need to understand the structure and their association with C3-convertases of proteins that are involved in complement regulation. Toward this goal we are investigating three regulatory viral proteins, vaccinia complement protein VCP, smallpox inhibitor of complement enzymes SPICE and Kaposi's sarcoma-associated herpes virus complement regulator KCP. We will investigate their individual structures and their complexes with C3b and C4b to understand the conformational changes induced by the regulatory proteins in controlling C3-convertases. The results from these structural studies will also help us understand the mechanisms evolved by viruses and bacteria to escape and evade the complement system and thereby survive and proliferate in host cells.

The second focus of our lab is to understand the mode of bacterial colonization; specifically by the Gram-positive bacteria, which are decorated with multiple types of surface proteins and proteinaceous pili extensions. Our interest is to understand not only the hosts complement response elicited by these intruders but also the tools used by pathogens for evade and escape the host response. Sortase is cysteine protease and conserved across Gram-positive bacteria, where specific and distinct sortases are used for surface protein anchoring and pili assembly respectively. We have revealed the structures of many surface proteins that are specifically directed towards distinct host proteins (collagen, fibrinogen, fibronectin, etc) and also their mode of binding and the structural correlates that dictate surface protein specificity. We have also determined the structures of sortases responsible for surface protein anchoring (Sortase A of S. aureus), iron acquisition (Sortase B of S. aureus), pili assembly (Sortase B of S. agalactiae) and pili anchoring (Sortase A S. agalactiae). We are probing the structural correlates of sortases that dictate the destiny of proteins, either to be anchored to cell surface or to be incorporated in pili. We are investigating the structures of individual pili components (SpaA and SpaB of S. agalactiae) and their multiple complexes. Our ultimate goal is to present a model for Gram-positive pili assembly and the mechanism of such assembly catalyzed by sortases. The results will provide means for human interference with virulence as opposed to bacterial growth, which is an approach for the prevention and treatment of bacterial infections that do not elicit multi-drug resistance.

Mark R. Walter, PhD The Walter lab is interested in protein-protein interactions and structural biology of macromolecular complexes required to elicit effective host immune responses against pathogens. Studies have focused on the IL-10 family (IL-10, IFN-γ, IL-20, IL-22, IL-24, IL-26, IL-28, and IL-29) of cytokine receptor complexes that play essential roles in the development and control of the adaptive immune response. The inter-cellular communication provided by these molecules is controlled by a dazzling array of protein-protein interactions that our lab is unraveling. We also study the structure and function of virally encoded proteins produced by herpesviruses and poxviruses that target the IL-10 family and allow the viruses to escape elimination by the immune system. Understanding the competing molecular strategies used by the host and virus to activate or deactivate the immune system may to lead novel ways of controlling chronic inflammation and/or improving the detection and elimination of persistent viral infections.

The lab performs the techniques required to answer mechanistic questions about molecular recognition, viral immune evasion, and cell signaling including protein biochemistry, X-ray crystallography, Surface Plasmon Resonance, computational and bioinformatic approaches, and structure-based functional assays in cells.