Molecular Modeling of Immunoglobulin Superfamily Proteins: Predicting the Three Dimensional Structure of the Extracellular Domain of CTLA-4 (CD152) |
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Authors: | Jürgen Bajorath Peter S Linsley |
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Institution: | 1. Bristol-Myers Squibb Pharmaceutical Research Institute, 3005 First Avenue, Seattle, WA, 98121, USA 2. Department of Biological Structure, University of Washington, Seattle, WA, 98195, USA
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Abstract: | The interactions between CD28/CTLA-4 (CD152) on T cells and their ligands CD80/CD86 on antigen presenting cells provide costimulatory signals critical for T cell activation. CD28/CTLA-4 and CD80/CD86 are members of the immunoglobulin superfamily (IgSF). CD28 and CTLA-4 both contain a single extracellular immunoglobulin (Ig) domain which binds CD80/CD86. Here we report modeling studies on the three-dimensional (3D) structure of the CTLA-4 binding domain. Since CTLA-4 displays only very weak sequence homology to proteins with known 3D structure, conventional modeling techniques were difficult to apply. Structure-oriented sequence comparison, consensus residue analysis, conformational searching, and inverse folding calculations were employed to aid in the generation of a comparative CTLA-4 model. Regions of high and low prediction confidence were identified, and the sequence-structure compatibility of the model was determined. Characteristics of the modeled structure, which resembles an Ig V domain, were analyzed, and the model was used to map N-linked glycosylation sites and residues critical for CTLA-4 function. The modeling approach described here can be applied to predict 3D structures of other IgSF proteins. |
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