PSI Structural Biology Knowledgebase

PSI | Structural Biology Knowledgebase
Header Icons

Related Articles
Drug Discovery: Solving the Structure of an Anti-hypertension Drug Target
July 2015
Retrospective: 7,000 Structures Closer to Understanding Biology
July 2015
Design and Evolution: Bespoke Design of Repeat Proteins
June 2015
Design and Evolution: Tunable Antibody Binders
June 2015
Immunity: Clustering Immunoglobulins
June 2014
Immunity: Conformational Capture
June 2014
Immunity: One Antibody to Rule Them All
June 2014
Immunity: Tissue Contribution
June 2014
Caught in the Act
December 2013
Serum Albumins and Allergies
October 2013
The Immune System: A Brotherhood of Immunoglobulins
June 2013
The Immune System: A Strong Competitor
June 2013
The Immune System: Strand Swapping for T-Cell Inhibition
June 2013
The Immune System: Super Cytokines
June 2013
Tuning Immune Response with Costimulation
June 2013
Regulatory insights
September 2012
Serum albumin diversity
August 2012
Substrate specificity sleuths
April 2012
February 2012
Analyzing an allergen
January 2012
TLR4 regulation: heads or tails?
October 2011
Binding complement with complementarity
June 2011

Research Themes Immunology

The Immune System: Strand Swapping for T-Cell Inhibition

SBKB [doi:10.1038/sbkb.2012.143]
Featured Article - June 2013
Short description: An immunoglobulin protein with a role in antigen-independent T-cell signaling dimerizes via a strand-swapped interface.

Ribbon diagram of the strand-swapped dimer of the IgV domain of mB7H3. Protomers are green and red, the β-strands yellow and the swapped G strand black. Reprinted with permission from Elsevier. 1

T-cell activation is dependent on the integration of both antigen-dependent signals through the T-cell receptor and antigen-independent interactions through ligands such as the B7 protein family.

Almo, Vigdorovich and colleagues (PSI NYSGRC) investigated the extracellular region of murine B7-H3 (mB7H3), a recently identified B7 protein implicated in various malignancies but of unclear precise function. Composed of a single IgV-IgC domain pair, mB7H3 was expressed in Drosophila cells as a glycosylated monomer. Notably, the authors obtained crystals only when using protein stocks that had been stored for several weeks and dimerized by a kinetically slow process. The 2.97-Å resolution structure (PDB 4I0K) revealed paired mB7H3 molecules with extensive interactions between the two IgV domains. Specifically, the segment connecting F and G strands (FG loop) of each IgV domain adopts an extended conformation, resulting in non-canonical strand swapping that mediates dimer formation. In contrast, the C-terminal IgC domain adopts the expected β-sandwich fold. Overall, the assembly spans ∼155 Å and the dimerization mode is distinct from that usually employed by the immunoglobulin superfamily.

The authors used the mB7H3 structure to construct a model for the monomeric form, which aligned favorably with PD-L1, a representative B7 structure. Next, they measured the effect of exogenously added mB7H3 to T-cell proliferation and observed a 50% decrease in the presence of freshly purified, monomeric wild-type mB7H3. Thus, mB7H3 can inhibit T-cell activation. Single alanine substitutions of FG loop residues had only minor effects on inhibitory activity, whereas replacement of the entire loop with the equivalent sequence from PD-L1 caused almost complete loss of activity, indicating that these residues interact with a T-cell receptor that remains to be identified.

The researchers further investigated the biophysical basis and functional effects of mB7H3 dimerization. Substitution of the four-residue sequence I(Q/R)DF in the mB7H3 FG loop with the equivalent, conserved YGGA sequence from PD-L1 significantly slowed dimerization. Furthermore, dimeric mB7H3 was similar to the monomeric form in its ability to inhibit T-cell proliferation. The authors note that, while such strand-swapped dimers are not unprecedented, their functional relevance has been unclear, as is the exact function of B7-H3. However, the functional importance of the FG loop residues represents an avenue for drug development.

Michael A. Durney


  1. V. Vigdorovich et al. Structure and T cell inhibition properties of B7 family member, B7-H3.
    Structure. 21, 1-11 (2013). doi:10.1016/j.str.2013.03.003

Structural Biology Knowledgebase ISSN: 1758-1338
Funded by a grant from the National Institute of General Medical Sciences of the National Institutes of Health