Secreted and cell-surface-localized Immunoglobulin Superfamily proteins (`extracellular IgSFs') are important class of proteins, which includes proven targets for the treatment of autoimmune diseases and cancer. The human proteome contains ~500 extracellular IgSFs, the largest superfamily of cell surface molecules that contribute to the regulation of innate and adaptive immunity, via specific IgSF:IgSF interactions at the `Immunological Synapse? formed between antigen-presenting cells and T-cells. Our long-term goal is to understand the principles underlying molecular recognition and selectivity at the immunological synapse through a multi-disciplinary program exploiting complementary computational and experimental approaches. These studies are essential to (i) understand the molecular basis of normal immune function associated with IgSFs; (ii) define the mechanisms underlying IgSF-associated dysfunction and disease, and (iii) define strategies to re-engineer IgSF receptor:ligand interactions for the realization of surgically defined mutants with altered affinities and selectivities, which can act as biologic drugs (as demonstrated by FDA-approved biologics for some of these targets such as Orencia? and Belatacept). Our goal in this application is (1) to identify the protein-protein binding sites specific for individual IgSF members; here, we will exploit our previously published approaches that combine structure and sequence information that identified functional subfamilies of the IgSF. We also present a new approach that identifies binding sites by their physico-chemical and spatial ?uniqueness? (2) Develop a protein design-aided pharmacophore approach to identify cognate receptor-ligand pairs of IgSFs; We present a new method that exploits the ligand-based pharmacophore drug design concept, where we characterize the receptor:ligand interface by a unique spatial fingerprint of energetically favorable `residue-specific-pharmacophores'. However, instead of ligand binding information here we use preferences of amino acid residues or residue fragments that are obtained from molecular dynamics simulations. (3) Experimentally verify predicted receptor-ligand partners and explore binding specificity of mutants. Our project will directly expand the current knowledgebase of IgSF:IgSF binding pairs and yield mutant molecules, with altered affinities and selectivities, for therapeutic applications. Our project will also deliver a protein-ligand screening tool applicable to other protein classes, and a novel `uniqueness'-driven hot-spot detection method for mutant design.
The immunological synapse formed between antigen presenting cells and T cells is a complex network of hundreds of protein ligand-receptor interactions that modulate the strength, course and duration of an immune response. This interdisciplinary proposal aims at developing novel computational techniques to identify cognate binding sites, and binding partners within the superfamily of cell surface anchored Immunoglobulin proteins that dominate these interactions and to experimentally verify these predictions. Deeper understanding of the molecular recognition mechanisms in the immunological synapse will provide invaluable insight to develop new biologic drugs for immunotherapy.
| Gil, Nelson; Fiser, Andras (2018) Identifying functionally informative evolutionary sequence profiles. Bioinformatics 34:1278-1286 |
| Yap, Eng-Hui; Fiser, Andras (2016) ProtLID, a Residue-Based Pharmacophore Approach to Identify Cognate Protein Ligands in the Immunoglobulin Superfamily. Structure 24:2217-2226 |
| Dybas, Joseph M; Fiser, Andras (2016) Development of a motif-based topology-independent structure comparison method to identify evolutionarily related folds. Proteins 84:1859-1874 |
