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Title: Structure of CD84 Provides Insight into SLAM Family Function

Abstract

The signaling lymphocyte activation molecule (SLAM) family includes homophilic and heterophilic receptors that modulate both adaptive and innate immune responses. These receptors share a common ectodomain organization: a membrane-proximal immunoglobulin constant domain and a membrane-distal immunoglobulin variable domain that is responsible for ligand recognition. CD84 is a homophilic family member that enhances IFN-{gamma} secretion in activated T cells. Our solution studies revealed that CD84 strongly self-associates with a K{sub d} in the submicromolar range. These data, in combination with previous reports, demonstrate that the SLAM family homophilic affinities span at least three orders of magnitude and suggest that differences in the affinities may contribute to the distinct signaling behavior exhibited by the individual family members. The 2.0 {angstrom} crystal structure of the human CD84 immunoglobulin variable domain revealed an orthogonal homophilic dimer with high similarity to the recently reported homophilic dimer of the SLAM family member NTB-A. Structural and chemical differences in the homophilic interfaces provide a mechanism to prevent the formation of undesired heterodimers among the SLAM family homophilic receptors. These structural data also suggest that, like NTB-A, all SLAM family homophilic dimers adopt a highly kinked organization spanning an end-to-end distance of {approx}140 {angstrom}. This common molecular dimensionmore » provides an opportunity for all two-domain SLAM family receptors to colocalize within the immunological synapse and bridge the T cell and antigen-presenting cell.« less

Authors:
; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
930439
Report Number(s):
BNL-81184-2008-JA
Journal ID: ISSN 0027-8424; PNASA6; TRN: US200904%%713
DOE Contract Number:  
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: Proceedings of the National Academy of Sciences of the USA; Journal Volume: 104; Journal Issue: 25
Country of Publication:
United States
Language:
English
Subject:
36 MATERIALS SCIENCE; CRYSTAL STRUCTURE; DIMERS; IMMUNOGLOBULINS; LYMPHOCYTES; PROTEINS; RECEPTORS; SECRETION; national synchrotron light source

Citation Formats

Yan,Q., Malashkevich, V., Fedorov, A., Fedorov, E., Cao, E., Lary, J., Cole, J., Nathenson, S., and Almo, S.. Structure of CD84 Provides Insight into SLAM Family Function. United States: N. p., 2007. Web. doi:10.1073/pnas.0703893104.
Yan,Q., Malashkevich, V., Fedorov, A., Fedorov, E., Cao, E., Lary, J., Cole, J., Nathenson, S., & Almo, S.. Structure of CD84 Provides Insight into SLAM Family Function. United States. doi:10.1073/pnas.0703893104.
Yan,Q., Malashkevich, V., Fedorov, A., Fedorov, E., Cao, E., Lary, J., Cole, J., Nathenson, S., and Almo, S.. Mon . "Structure of CD84 Provides Insight into SLAM Family Function". United States. doi:10.1073/pnas.0703893104.
@article{osti_930439,
title = {Structure of CD84 Provides Insight into SLAM Family Function},
author = {Yan,Q. and Malashkevich, V. and Fedorov, A. and Fedorov, E. and Cao, E. and Lary, J. and Cole, J. and Nathenson, S. and Almo, S.},
abstractNote = {The signaling lymphocyte activation molecule (SLAM) family includes homophilic and heterophilic receptors that modulate both adaptive and innate immune responses. These receptors share a common ectodomain organization: a membrane-proximal immunoglobulin constant domain and a membrane-distal immunoglobulin variable domain that is responsible for ligand recognition. CD84 is a homophilic family member that enhances IFN-{gamma} secretion in activated T cells. Our solution studies revealed that CD84 strongly self-associates with a K{sub d} in the submicromolar range. These data, in combination with previous reports, demonstrate that the SLAM family homophilic affinities span at least three orders of magnitude and suggest that differences in the affinities may contribute to the distinct signaling behavior exhibited by the individual family members. The 2.0 {angstrom} crystal structure of the human CD84 immunoglobulin variable domain revealed an orthogonal homophilic dimer with high similarity to the recently reported homophilic dimer of the SLAM family member NTB-A. Structural and chemical differences in the homophilic interfaces provide a mechanism to prevent the formation of undesired heterodimers among the SLAM family homophilic receptors. These structural data also suggest that, like NTB-A, all SLAM family homophilic dimers adopt a highly kinked organization spanning an end-to-end distance of {approx}140 {angstrom}. This common molecular dimension provides an opportunity for all two-domain SLAM family receptors to colocalize within the immunological synapse and bridge the T cell and antigen-presenting cell.},
doi = {10.1073/pnas.0703893104},
journal = {Proceedings of the National Academy of Sciences of the USA},
number = 25,
volume = 104,
place = {United States},
year = {Mon Jan 01 00:00:00 EST 2007},
month = {Mon Jan 01 00:00:00 EST 2007}
}