TY - JOUR
T1 - Functional classification of immune regulatory proteins
AU - Rubinstein, Rotem
AU - Ramagopal, Udupi A.
AU - Nathenson, Stanley G.
AU - Almo, Steven C.
AU - Fiser, Andras
N1 - Funding Information:
We are grateful to Drs. Eduardo Fajardo, Rafael Toro, Chenyang Zhan, and Michael Brenowitz for their help with informatics, crystallization, crystallography, and analytical ultracentrifugation, respectively. We gratefully acknowledge the staff of the X29 beamline at the National Synchrotron Light Source for their assistance in data collection. This work was supported by grants from the National Institutes of Health (GM094665, GM094662, AI007289, GM096041, and CA013330).
Funding Information:
Based on the mechanistic and therapeutic importance of these molecules, a systematic structural analysis of the entire ensemble of cell-surface immune regulatory proteins and their cognate complexes remains one of the major goals of structural immunology. Indeed, large-scale efforts are now beginning to focus on this task, including the SPINE2 program supported by the European Commission ( http://www.spine2.eu ) and the Immune Function Network supported by National Institutes of Health Protein Structure Initiative ( http://sbkb.org/kb/centers.jsp?pageshow=20 ). However, given that the number of targets is estimated to be in the thousands (considering all full-length proteins, protein domains, and protein complexes involved in the immune response), it remains impractical for one laboratory, or even a substantial consortium of laboratories, to structurally and functionally characterize all targets. These goals are further complicated by the fact that many of the biologically important receptor-ligand interactions remain unknown. Therefore, there exists a need to develop complementary strategies to identify, select, and prioritize protein targets for experimental analysis.
PY - 2013/5/7
Y1 - 2013/5/7
N2 - The members of the immunoglobulin superfamily (IgSF) control innate and adaptive immunity and are prime targets for the treatment of autoimmune diseases, infectious diseases, and malignancies. We describe a computational method, termed the Brotherhood algorithm, which utilizes intermediate sequence information to classify proteins into functionally related families. This approach identifies functional relationships within the IgSF and predicts additional receptor-ligand interactions. As a specific example, we examine the nectin/nectin-like family of cell adhesion and signaling proteins and propose receptor-ligand interactions within this family. Guided by the Brotherhood approach, we present the high-resolution structural characterization of a homophilic interaction involving the class-I MHC-restricted T-cell-associated molecule, which we now classify as a nectin-like family member. The Brotherhood algorithm is likely to have a significant impact on structural immunology by identifying those proteins and complexes for which structural characterization will be particularly informative.
AB - The members of the immunoglobulin superfamily (IgSF) control innate and adaptive immunity and are prime targets for the treatment of autoimmune diseases, infectious diseases, and malignancies. We describe a computational method, termed the Brotherhood algorithm, which utilizes intermediate sequence information to classify proteins into functionally related families. This approach identifies functional relationships within the IgSF and predicts additional receptor-ligand interactions. As a specific example, we examine the nectin/nectin-like family of cell adhesion and signaling proteins and propose receptor-ligand interactions within this family. Guided by the Brotherhood approach, we present the high-resolution structural characterization of a homophilic interaction involving the class-I MHC-restricted T-cell-associated molecule, which we now classify as a nectin-like family member. The Brotherhood algorithm is likely to have a significant impact on structural immunology by identifying those proteins and complexes for which structural characterization will be particularly informative.
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U2 - 10.1016/j.str.2013.02.022
DO - 10.1016/j.str.2013.02.022
M3 - Article
C2 - 23583034
AN - SCOPUS:84877293417
SN - 0969-2126
VL - 21
SP - 766
EP - 776
JO - Structure
JF - Structure
IS - 5
ER -
