PDBsum entry 1xu2

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protein metals Protein-protein interface(s) links
Cytokine, hormone/growth factor receptor PDB id
Protein chains
137 a.a. *
36 a.a. *
37 a.a. *
35 a.a. *
Waters ×36
* Residue conservation analysis
PDB id:
Name: Cytokine, hormone/growth factor receptor
Title: The crystal structure of april bound to bcma
Structure: Tumor necrosis factor ligand superfamily member 1 chain: a, b, d. Fragment: tnf domain of april. Synonym: a proliferation-inducing ligand, april, tnfsf13b o engineered: yes. Tumor necrosis factor receptor superfamily member chain: r, s, t. Fragment: bcma ecd. Synonym: b-cell maturation protein, tnffsf17.
Source: Mus musculus. House mouse. Organism_taxid: 10090. Gene: tnfsf13, april. Expressed in: escherichia coli. Expression_system_taxid: 562. Homo sapiens. Human. Organism_taxid: 9606.
Biol. unit: Hexamer (from PQS)
2.35Å     R-factor:   0.182     R-free:   0.213
Authors: S.G.Hymowitz,D.R.Patel,H.J.A.Wallweber,S.Runyon,M.Yan,J.Yin, S.K.Shriver,N.C.Gordon,B.Pan,N.J.Skelton,R.F.Kelley,M.A.Sta
Key ref:
S.G.Hymowitz et al. (2005). Structures of APRIL-receptor complexes: like BCMA, TACI employs only a single cysteine-rich domain for high affinity ligand binding. J Biol Chem, 280, 7218-7227. PubMed id: 15542592 DOI: 10.1074/jbc.M411714200
25-Oct-04     Release date:   09-Nov-04    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
Q9D777  (TNF13_MOUSE) -  Tumor necrosis factor ligand superfamily member 13
241 a.a.
137 a.a.
Protein chain
Pfam   ArchSchema ?
Q02223  (TNR17_HUMAN) -  Tumor necrosis factor receptor superfamily member 17
184 a.a.
36 a.a.
Protein chain
Pfam   ArchSchema ?
Q02223  (TNR17_HUMAN) -  Tumor necrosis factor receptor superfamily member 17
184 a.a.
37 a.a.
Protein chain
Pfam   ArchSchema ?
Q02223  (TNR17_HUMAN) -  Tumor necrosis factor receptor superfamily member 17
184 a.a.
35 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     membrane   1 term 
  Biological process     immune response   1 term 
  Biochemical function     tumor necrosis factor receptor binding     1 term  


DOI no: 10.1074/jbc.M411714200 J Biol Chem 280:7218-7227 (2005)
PubMed id: 15542592  
Structures of APRIL-receptor complexes: like BCMA, TACI employs only a single cysteine-rich domain for high affinity ligand binding.
S.G.Hymowitz, D.R.Patel, H.J.Wallweber, S.Runyon, M.Yan, J.Yin, S.K.Shriver, N.C.Gordon, B.Pan, N.J.Skelton, R.F.Kelley, M.A.Starovasnik.
TACI is a member of the tumor necrosis factor receptor superfamily and serves as a key regulator of B cell function. TACI binds two ligands, APRIL and BAFF, with high affinity and contains two cysteine-rich domains (CRDs) in its extracellular region; in contrast, BCMA and BR3, the other known high affinity receptors for APRIL and BAFF, respectively, contain only a single or partial CRD. However, another form of TACI exists wherein the N-terminal CRD is removed by alternative splicing. We find that this shorter form is capable of ligand-induced cell signaling and that the second CRD alone (TACI_d2) contains full affinity for both ligands. Furthermore, we report the solution structure and alanine-scanning mutagenesis of TACI_d2 along with co-crystal structures of APRIL.TACI_d2 and APRIL.BCMA complexes that together reveal the mechanism by which TACI engages high affinity ligand binding through a single CRD, and we highlight sources of ligand-receptor specificity within the APRIL/BAFF system.
  Selected figure(s)  
Figure 5.
FIG. 5. Crystal structures of APRIL-receptor complexes. A, ribbon structure of APRIL·TACI_d2 complex. The APRIL trimer (residues 105-241) is shown in gray, yellow, and pink, and the three copies of TACI_d2 are colored blue. In this orientation, the membrane of the TACI-presenting cell would be located at the bottom of the figure. B, comparison of APRIL-receptor complexes. The DXL motif, h1 and the h1h2 loop, are shown for both TACI_d2 (blue) and BCMA (yellow, labels underlined). Side chains from APRIL (white, labels italicized) which interact with receptor are rendered as sticks. C, comparison of TACI_d2, BCMA, and BR3. Ribbon drawings of the three receptors for APRIL and/or BAFF are shown superimposed using the backbone atoms of residues in the DXL motif (residues 79-85, 14-20, and 25-31 in TACI_d2, BCMA, and BR3, respectively). The TACI_d2 (blue) and BCMA (yellow) structures are taken from the crystal structures of their respective APRIL-receptor complex, whereas the BR3 (green) structure is from the crystal structure of the BAFF·BR3 complex, 1OQE (26).
Figure 7.
FIG. 7. Evolution of the TNFR superfamily. Sketch of the possible steps in the evolution of BR3-like, BCMA-like, and multidomain TNFR-like receptors from an ancestral single domain receptor. TACI-like receptors with two CRDs, one of which is less functional, may represent a crucial step between single-domain and specialized multidomain receptors.
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2005, 280, 7218-7227) copyright 2005.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21458042 C.Bacchelli, K.F.Buckland, S.Buckridge, U.Salzer, P.Schneider, A.J.Thrasher, and H.B.Gaspar (2011).
The C76R transmembrane activator and calcium modulator cyclophilin ligand interactor mutation disrupts antibody production and B-cell homeostasis in heterozygous and homozygous mice.
  J Allergy Clin Immunol, 127, 1253.  
  20184394 Y.Kanno, D.Sakurai, H.Hase, H.Kojima, and T.Kobata (2010).
TACI induces cIAP1-mediated ubiquitination of NIK by TRAF2 and TANK to limit non-canonical NF-kappaB signaling.
  J Recept Signal Transduct Res, 30, 121-132.  
19286389 E.Roosnek, M.Burjanadze, P.Y.Dietrich, T.Matthes, J.Passweg, and B.Huard (2009).
Tumors that look for their springtime in APRIL.
  Crit Rev Oncol Hematol, 72, 91-97.  
19241374 F.He, W.Dang, K.Saito, S.Watanabe, N.Kobayashi, P.Güntert, T.Kigawa, A.Tanaka, Y.Muto, and S.Yokoyama (2009).
Solution structure of the cysteine-rich domain in Fn14, a member of the tumor necrosis factor receptor superfamily.
  Protein Sci, 18, 650-656.
PDB code: 2rpj
19521398 F.Mackay, and P.Schneider (2009).
Cracking the BAFF code.
  Nat Rev Immunol, 9, 491-502.  
19034695 J.F.Treml, Y.Hao, J.E.Stadanlick, and M.P.Cancro (2009).
The BLyS family: toward a molecular understanding of B cell homeostasis.
  Cell Biochem Biophys, 53, 1.  
19605846 J.J.Lee, I.Rauter, L.Garibyan, E.Ozcan, T.Sannikova, S.R.Dillon, A.C.Cruz, R.M.Siegel, R.Bram, H.Jabara, and R.S.Geha (2009).
The murine equivalent of the A181E TACI mutation associated with common variable immunodeficiency severely impairs B-cell function.
  Blood, 114, 2254-2262.  
19629655 J.Mohammadi, C.Liu, A.Aghamohammadi, A.Bergbreiter, L.Du, J.Lu, N.Rezaei, A.A.Amirzargar, M.Moin, U.Salzer, Q.Pan-Hammarström, and L.Hammarström (2009).
Novel mutations in TACI (TNFRSF13B) causing common variable immunodeficiency.
  J Clin Immunol, 29, 777-785.  
  19147815 M.Razmara, B.Hilliard, A.K.Ziarani, R.Murali, S.Yellayi, M.Ghazanfar, Y.H.Chen, and M.L.Tykocinski (2009).
Fn14-TRAIL, a chimeric intercellular signal exchanger, attenuates experimental autoimmune encephalomyelitis.
  Am J Pathol, 174, 460-474.  
20161663 R.F.Parsons, K.Vivek, R.R.Redfield, T.S.Migone, M.P.Cancro, A.Naji, and H.Noorchashm (2009).
B-cell tolerance in transplantation: is repertoire remodeling the answer?
  Expert Rev Clin Immunol, 5, 703.  
20477641 S.Ahn, and C.Cunningham-Rundles (2009).
Role of B cells in common variable immune deficiency.
  Expert Rev Clin Immunol, 5, 557-564.  
18981294 U.Salzer, C.Bacchelli, S.Buckridge, Q.Pan-Hammarström, S.Jennings, V.Lougaris, A.Bergbreiter, T.Hagena, J.Birmelin, A.Plebani, A.D.Webster, H.H.Peter, D.Suez, H.Chapel, A.McLean-Tooke, G.P.Spickett, S.Anover-Sombke, H.D.Ochs, S.Urschel, B.H.Belohradsky, S.Ugrinovic, D.S.Kumararatne, T.C.Lawrence, A.M.Holm, J.L.Franco, I.Schulze, P.Schneider, E.M.Gertz, A.A.Schäffer, L.Hammarström, A.J.Thrasher, H.B.Gaspar, and B.Grimbacher (2009).
Relevance of biallelic versus monoallelic TNFRSF13B mutations in distinguishing disease-causing from risk-increasing TNFRSF13B variants in antibody deficiency syndromes.
  Blood, 113, 1967-1976.  
19466596 W.Ding, S.Ju, S.Jiang, L.Zhu, Y.Wang, and H.Wang (2009).
Reduced APRIL expression induces cellular senescence via a HSPG-dependent pathway.
  Pathol Oncol Res, 15, 693-701.  
18613837 C.F.Ware (2008).
Targeting lymphocyte activation through the lymphotoxin and LIGHT pathways.
  Immunol Rev, 223, 186-201.  
18668213 J.E.Crowley, J.L.Scholz, W.J.Quinn Iii, J.E.Stadanlick, J.F.Treml, L.S.Treml, Y.Hao, R.Goenka, P.J.O'Neill, A.H.Matthews, R.F.Parsons, and M.P.Cancro (2008).
Homeostatic control of B lymphocyte subsets.
  Immunol Res, 42, 75-83.  
18978466 J.J.Lee, E.Ozcan, I.Rauter, and R.S.Geha (2008).
Transmembrane activator and calcium-modulator and cyclophilin ligand interactor mutations in common variable immunodeficiency.
  Curr Opin Allergy Clin Immunol, 8, 520-526.  
17556024 A.K.Knight, L.Radigan, T.Marron, A.Langs, L.Zhang, and C.Cunningham-Rundles (2007).
High serum levels of BAFF, APRIL, and TACI in common variable immunodeficiency.
  Clin Immunol, 124, 182-189.  
17917015 E.Castigli, and R.S.Geha (2007).
TACI, isotype switching, CVID and IgAD.
  Immunol Res, 38, 102-111.  
17140663 I.Debnath, K.M.Roundy, J.J.Weis, and J.H.Weis (2007).
Analysis of the regulatory role of BAFF in controlling the expression of CD21 and CD23.
  Mol Immunol, 44, 2388-2399.  
17492055 L.Garibyan, A.A.Lobito, R.M.Siegel, M.E.Call, K.W.Wucherpfennig, and R.S.Geha (2007).
Dominant-negative effect of the heterozygous C104R TACI mutation in common variable immunodeficiency (CVID).
  J Clin Invest, 117, 1550-1557.  
17983875 L.Zhang, L.Radigan, U.Salzer, T.W.Behrens, B.Grimbacher, G.Diaz, J.Bussel, and C.Cunningham-Rundles (2007).
Transmembrane activator and calcium-modulating cyclophilin ligand interactor mutations in common variable immunodeficiency: clinical and immunologic outcomes in heterozygotes.
  J Allergy Clin Immunol, 120, 1178-1185.  
17500026 S.S.Sidhu, and A.A.Kossiakoff (2007).
Exploring and designing protein function with restricted diversity.
  Curr Opin Chem Biol, 11, 347-354.  
17464555 U.Salzer, J.Birmelin, C.Bacchelli, T.Witte, U.Buchegger-Podbielski, S.Buckridge, R.Rzepka, H.B.Gaspar, A.J.Thrasher, R.E.Schmidt, I.Melchers, and B.Grimbacher (2007).
Sequence analysis of TNFRSF13b, encoding TACI, in patients with systemic lupus erythematosus.
  J Clin Immunol, 27, 372-377.  
17171762 U.Salzer, S.Jennings, and B.Grimbacher (2007).
To switch or not to switch--the opposing roles of TACI in terminal B cell differentiation.
  Eur J Immunol, 37, 17-20.  
16914324 C.Bossen, and P.Schneider (2006).
BAFF, APRIL and their receptors: structure, function and signaling.
  Semin Immunol, 18, 263-275.  
16919470 L.S.Treml, J.E.Crowley, and M.P.Cancro (2006).
BLyS receptor signatures resolve homeostatically independent compartments among naïve and antigen-experienced B cells.
  Semin Immunol, 18, 297-304.  
17038469 M.P.Cancro (2006).
The BLyS/BAFF family of ligands and receptors: key targets in the therapy and understanding of autoimmunity.
  Ann Rheum Dis, 65, iii34-iii36.  
17125150 R.L.Rich, and D.G.Myszka (2006).
Survey of the year 2005 commercial optical biosensor literature.
  J Mol Recognit, 19, 478-534.  
16474316 S.R.Dillon, J.A.Gross, S.M.Ansell, and A.J.Novak (2006).
An APRIL to remember: novel TNF ligands as therapeutic targets.
  Nat Rev Drug Discov, 5, 235-246.  
17023177 U.Salzer, and B.Grimbacher (2006).
Common variable immunodeficiency: The power of co-stimulation.
  Semin Immunol, 18, 337-346.  
16007086 E.Castigli, S.A.Wilson, L.Garibyan, R.Rachid, F.Bonilla, L.Schneider, and R.S.Geha (2005).
TACI is mutant in common variable immunodeficiency and IgA deficiency.
  Nat Genet, 37, 829-834.  
16049503 F.Martin, and V.M.Dixit (2005).
Unraveling TACIt functions.
  Nat Genet, 37, 793-794.  
15851487 K.Ingold, A.Zumsteg, A.Tardivel, B.Huard, Q.G.Steiner, T.G.Cachero, F.Qiang, L.Gorelik, S.L.Kalled, H.Acha-Orbea, P.D.Rennert, J.Tschopp, and P.Schneider (2005).
Identification of proteoglycans as the APRIL-specific binding partners.
  J Exp Med, 201, 1375-1383.  
15886118 P.Schneider (2005).
The role of APRIL and BAFF in lymphocyte activation.
  Curr Opin Immunol, 17, 282-289.  
16370373 S.Fournel, S.Wieckowski, W.Sun, N.Trouche, H.Dumortier, A.Bianco, O.Chaloin, M.Habib, J.C.Peter, P.Schneider, B.Vray, R.E.Toes, R.Offringa, C.J.Melief, J.Hoebeke, and G.Guichard (2005).
C3-symmetric peptide scaffolds are functional mimetics of trimeric CD40L.
  Nat Chem Biol, 1, 377-382.  
16276047 T.Matsushita, and S.Sato (2005).
[The role of BAFF in autoimmune diseases]
  Nihon Rinsho Meneki Gakkai Kaishi, 28, 333-342.  
16264328 U.Salzer, and B.Grimbacher (2005).
TACItly changing tunes: farewell to a yin and yang of BAFF receptor and TACI in humoral immunity? New genetic defects in common variable immunodeficiency.
  Curr Opin Allergy Clin Immunol, 5, 496-503.  
16007087 U.Salzer, H.M.Chapel, A.D.Webster, Q.Pan-Hammarström, A.Schmitt-Graeff, M.Schlesier, H.H.Peter, J.K.Rockstroh, P.Schneider, A.A.Schäffer, L.Hammarström, and B.Grimbacher (2005).
Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans.
  Nat Genet, 37, 820-828.  
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. Where a reference describes a PDB structure, the PDB code is shown on the right.