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PDBsum entry 2aw2
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protein ligands metals Protein-protein interface(s) links
Immune system PDB id
2aw2

 

 

 

 

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Contents
Protein chains
110 a.a. *
100 a.a. *
Ligands
NAG-NAG
NAG-FUL
Metals
_NI
Waters ×4
* Residue conservation analysis
PDB id:
2aw2
Name: Immune system
Title: Crystal structure of the human btla-hvem complex
Structure: B and t lymphocyte attenuator. Chain: a, x. Fragment: extracellular domain (residues 26-137). Synonym: b and t lymphocyte-associated protein. Engineered: yes. Tumor necrosis factor receptor superfamily member 14. Chain: b, y. Fragment: truncated extracellular domain contains crd1, 2 and part of crd3 (residues 39-142).
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: btla. Expressed in: escherichia coli. Expression_system_taxid: 562. Gene: tnfrsf14, hvea, hvem. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.
Biol. unit: Dimer (from PQS)
Resolution:
2.80Å     R-factor:   0.236     R-free:   0.278
Authors: D.M.Compaan,L.C.Gonzalez,I.Tom,K.M.Loyet,D.Eaton,S.G.Hymowitz
Key ref:
D.M.Compaan et al. (2005). Attenuating lymphocyte activity: the crystal structure of the BTLA-HVEM complex. J Biol Chem, 280, 39553-39561. PubMed id: 16169851 DOI: 10.1074/jbc.M507629200
Date:
31-Aug-05     Release date:   27-Sep-05    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q7Z6A9  (BTLA_HUMAN) -  B- and T-lymphocyte attenuator from Homo sapiens
Seq:
Struc: 		289 a.a.
110 a.a.*
Protein chains
Pfam   ArchSchema ?
Q92956  (TNR14_HUMAN) -  Tumor necrosis factor receptor superfamily member 14 from Homo sapiens
Seq:
Struc: 		283 a.a.
100 a.a.
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 6 residue positions (black crosses)

 

 
DOI no: 10.1074/jbc.M507629200 J Biol Chem 280:39553-39561 (2005)
PubMed id: 16169851  
 
 
Attenuating lymphocyte activity: the crystal structure of the BTLA-HVEM complex.
D.M.Compaan, L.C.Gonzalez, I.Tom, K.M.Loyet, D.Eaton, S.G.Hymowitz.
 
  ABSTRACT  
 
Five CD28-like proteins exert positive or negative effects on immune cells. Only four of these five receptors interact with members of the B7 family. The exception is BTLA (B and T lymphocyte attenuator), which instead interacts with the tumor necrosis factor receptor superfamily member HVEM (herpes virus entry mediator). To better understand this interaction, we determined the 2.8-A crystal structure of the BTLA-HVEM complex. This structure shows that BTLA binds the N-terminal cysteine-rich domain of HVEM and employs a unique binding surface compared with other CD28-like receptors. Moreover, the structure shows that BTLA recognizes the same surface on HVEM as gD (herpes virus glycoprotein D) and utilizes a similar binding motif. Light scattering analysis demonstrates that the extracellular domain of BTLA is monomeric and that BTLA and HVEM form a 1:1 complex. Alanine-scanning mutagenesis of HVEM was used to further define critical binding residues. Finally, BTLA adopts an immunoglobulin I-set fold. Despite structural similarities to other CD28-like members, BTLA represents a unique co-receptor.
 
  Selected figure(s)  
 
Figure 1.
FIGURE 1. Complex of BTLA with HVEM. a, C- rendering of BTLA (yellow) and HVEM (CRD1, white; CRD2; light blue; CRD3, blue) showing that BTLA binds the N-terminal cysteine-rich domain of HVEM. sheets are shown as arrows. Cysteine residues are shows as sticks with the sulfur atoms colored orange. b, C- rendering of BTLA with strands labeled. C- atoms of predicted N-glycosylation sites are shown as purple spheres. c, wall-eyed stereo image of the BTLA-HVEM binding site showing the sheet hydrogen bonding pattern formed at the interface. Residues of interest are labeled. BTLA residues are underlined. 		Figure 4.
FIGURE 4. gD mimics BTLA. a, molecular surface of HVEM (CDR1 white; CRD2, light blue; CRD3, blue) is shown with C- renderings of BTLA. HVEM residues crucial for BTLA affinity (P17, V36, and Y23) are colored red and labeled. b, molecular surface of HVEM colored as in a with C- rendering of gD (N- and C-terminal extensions, yellow; Ig domain, green). HVEM residues crucial for gD affinity (C37 and Y23 (28)) are colored red and labeled. c, sequence of the structurally similar short -strands in BTLA and gD that bind HVEM.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2005, 280, 39553-39561) copyright 2005.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21283640 M.Yoon, S.J.Kopp, J.M.Taylor, C.S.Storti, P.G.Spear, and W.J.Muller (2011).
Functional Interaction between Herpes Simplex Virus Type 2 gD and HVEM Transiently Dampens Local Chemokine Production after Murine Mucosal Infection.
  PLoS One, 6, e16122.  
21078085 M.Zhang, K.Howard, A.Winters, S.Steavenson, S.Anderson, S.Smelt, G.Doellgast, C.Sheelo, J.Stevens, H.Kim, A.Hamburger, A.Sein, D.J.Caughey, F.Lee, H.Hsu, G.Siu, and F.R.Byrne (2011).
Monoclonal antibodies to B and T lymphocyte attenuator (BTLA) have no effect on in vitro B cell proliferation and act to inhibit in vitro T cell proliferation when presented in a cis, but not trans, format relative to the activating stimulus.
  Clin Exp Immunol, 163, 77-87.  
  21042564 L.Xia, S.Zhang, J.Zhou, and Y.Li (2010).
A crucial role for B and T lymphocyte attenuator in preventing the development of CD4+ T cell-mediated herpetic stromal keratitis.
  Mol Vis, 16, 2071-2083.  
20307212 T.L.Murphy, and K.M.Murphy (2010).
Slow down and survive: Enigmatic immunoregulation by BTLA and HVEM.
  Annu Rev Immunol, 28, 389-411.  
19426226 G.Cai, and G.J.Freeman (2009).
The CD160, BTLA, LIGHT/HVEM pathway: a bidirectional switch regulating T-cell activation.
  Immunol Rev, 229, 244-258.  
19426220 K.H.Yi, and L.Chen (2009).
Fine tuning the immune response through B7-H3 and B7-H4.
  Immunol Rev, 229, 145-151.  
19495760 M.W.Steinberg, J.W.Shui, C.F.Ware, and M.Kronenberg (2009).
Regulating the mucosal immune system: the contrasting roles of LIGHT, HVEM, and their various partners.
  Semin Immunopathol, 31, 207-221.  
19915044 T.C.Cheung, L.M.Oborne, M.W.Steinberg, M.G.Macauley, S.Fukuyama, H.Sanjo, C.D'Souza, P.S.Norris, K.Pfeffer, K.M.Murphy, M.Kronenberg, P.G.Spear, and C.F.Ware (2009).
T cell intrinsic heterodimeric complexes between HVEM and BTLA determine receptivity to the surrounding microenvironment.
  J Immunol, 183, 7286-7296.  
19332782 T.C.Cheung, M.W.Steinberg, L.M.Oborne, M.G.Macauley, S.Fukuyama, H.Sanjo, C.D'Souza, P.S.Norris, K.Pfeffer, K.M.Murphy, M.Kronenberg, P.G.Spear, and C.F.Ware (2009).
Unconventional ligand activation of herpesvirus entry mediator signals cell survival.
  Proc Natl Acad Sci U S A, 106, 6244-6249.  
19426215 T.Pentcheva-Hoang, E.Corse, and J.P.Allison (2009).
Negative regulators of T-cell activation: potential targets for therapeutic intervention in cancer, autoimmune disease, and persistent infections.
  Immunol Rev, 229, 67-87.  
  18097025 C.De Trez, K.Schneider, K.Potter, N.Droin, J.Fulton, P.S.Norris, S.W.Ha, Y.X.Fu, T.Murphy, K.M.Murphy, K.Pfeffer, C.A.Benedict, and C.F.Ware (2008).
The inhibitory HVEM-BTLA pathway counter regulates lymphotoxin receptor signaling to achieve homeostasis of dendritic cells.
  J Immunol, 180, 238-248.  
18613837 C.F.Ware (2008).
Targeting lymphocyte activation through the lymphotoxin and LIGHT pathways.
  Immunol Rev, 223, 186-201.  
18193050 G.Cai, A.Anumanthan, J.A.Brown, E.A.Greenfield, B.Zhu, and G.J.Freeman (2008).
CD160 inhibits activation of human CD4+ T cells through interaction with herpesvirus entry mediator.
  Nat Immunol, 9, 176-185.  
18204424 J.Kaye (2008).
CD160 and BTLA: LIGHTs out for CD4+ T cells.
  Nat Immunol, 9, 122-124.  
18949019 J.R.Sedý, P.G.Spear, and C.F.Ware (2008).
Cross-regulation between herpesviruses and the TNF superfamily members.
  Nat Rev Immunol, 8, 861-873.  
18193057 M.O.Lasaro, N.Tatsis, S.E.Hensley, J.C.Whitbeck, S.W.Lin, J.J.Rux, E.J.Wherry, G.H.Cohen, R.J.Eisenberg, and H.C.Ertl (2008).
Targeting of antigen to the herpesvirus entry mediator augments primary adaptive immune responses.
  Nat Med, 14, 205-212.  
18671825 M.T.Sciortino, M.A.Medici, F.Marino-Merlo, D.Zaccaria, M.Giuffrè-Cuculletto, A.Venuti, S.Grelli, and A.Mastino (2008).
Involvement of HVEM receptor in activation of nuclear factor kappaB by herpes simplex virus 1 glycoprotein D.
  Cell Microbiol, 10, 2297-2311.  
18500231 W.Zou, and L.Chen (2008).
Inhibitory B7-family molecules in the tumour microenvironment.
  Nat Rev Immunol, 8, 467-477.  
17206146 C.Krieg, O.Boyman, Y.X.Fu, and J.Kaye (2007).
B and T lymphocyte attenuator regulates CD8+ T cell-intrinsic homeostasis and memory cell generation.
  Nat Immunol, 8, 162-171.  
17449225 C.Zeng, Y.Zhen, S.A.Shu, T.Wu, H.Yi, Z.X.Lian, and Y.Zhao (2007).
The influence of cyclosporin A on lymphocyte attenuator expression.
  J Autoimmun, 28, 234-244.  
17607320 T.H.Wu, Y.Zhen, C.Zeng, H.F.Yi, and Y.Zhao (2007).
B and T lymphocyte attenuator interacts with CD3zeta and inhibits tyrosine phosphorylation of TCRzeta complex during T-cell activation.
  Immunol Cell Biol, 85, 590-595.  
16730267 A.J.Korman, K.S.Peggs, and J.P.Allison (2006).
Checkpoint blockade in cancer immunotherapy.
  Adv Immunol, 90, 297-339.  
16807107 A.Kinkade, and C.F.Ware (2006).
The DARC conspiracy--virus invasion tactics.
  Trends Immunol, 27, 362-367.  
16932752 K.M.Murphy, C.A.Nelson, and J.R.Sedý (2006).
Balancing co-stimulation and inhibition with BTLA and HVEM.
  Nat Rev Immunol, 6, 671-681.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time.

 

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