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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}
}
  • No abstract prepared.
  • Bacteria switch the direction their flagella rotate to control movement. FliM, along with FliN and FliG, compose a complex in the motor that, upon binding phosphorylated CheY, reverses the sense of flagellar rotation. The 2.0- Angstroms resolution structure of the FliM middle domain (FliMM) from Thermotoga maritima reveals a pseudo-2-fold symmetric topology similar to the CheY phosphatases CheC and CheX. A variable structural element, which, in CheC, mediates binding to CheD ({alpha}2') and, in CheX, mediates dimerization ({beta}x), has a truncated structure unique to FliM ({alpha}2'). An exposed helix of FliMM ({alpha}1) does not contain the catalytic residues of CheCmore » and CheX but does include positions conserved in FliM sequences. Cross-linking experiments with site-directed cysteine mutants show that FliM self-associates through residues on {alpha}1 and {alpha}2'. CheY activated by BeF3- binds to FliM with {approx}40-fold higher affinity than CheY (Kd = 0.04 {micro}M vs. 2 {micro}M). Mapping residue conservation, suppressor mutation sites, binding data, and deletion analysis onto the FliMM surface defines regions important for contacts with the stator-interacting protein FliG and for either counterclockwise or clockwise rotation. Association of 33-35 FliM subunits would generate a 44- to 45-nm-diameter disk, consistent with the known dimensions of the C-ring. The localization of counterclockwise- and clockwise-biasing mutations to distinct surfaces suggests that the binding of phosphorylated CheY cooperatively realigns FliM around the ring.« less
  • Serum transferrin reversibly binds iron in each of two lobes and delivers it to cells by a receptor-mediated, pH-dependant process. The binding and release of iron results in a large conformational change in which two subdomains in each lobe close or open with a rigid twisting motion around a hinge. We report the structure of human serum transferrin (hTF) lacking iron (apo-hTF) which was independently determined by two methods: (1) the crystal structure of recombinant non-glycosylated apo-hTF was solved at 2.7 Angstroms resolution using a MAD phasing strategy, by substituting the nine methionines in hTF with selenomethionine and (2) themore » structure of glycosylated apo-hTF (isolated from serum) was determined to a resolution of 2.7 Angstroms by molecular replacement using the human apo-N-lobe and the rabbit holo-C1-subdomain as search models. These two crystal structures are essentially identical. They represent the first published model for full-length human TF and reveal that, in contrast to family members (human lactoferrin and hen ovotransferrin), both lobes are almost equally open: 59.4 deg and 49.5 deg rotations are required to open the N- and C-lobe, respectively, (compared to closed pig TF). Availability of this structure is critical to a complete understanding of the metal binding properties of each lobe of hTF; the apo-hTF structure suggests that differences in the hinge regions of the N- and C-lobes may influence the rates of iron binding and release. In addition, we evaluate potential interactions between apo-hTF and the human transferrin receptor.« less