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3qd6

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3qd6, resolution 3.50Å ()
Ligands:
Gene: CD154, CD40L (Homo sapiens), CD40 (Homo sapiens)


Resources: FirstGlance, OCA, RCSB, PDBsum
Coordinates: save as pdb, mmCIF, xml


Contents

Crystal structure of the CD40 and CD154 (CD40L) complex

Publication Abstract from PubMed

CD40 is a tumor necrosis factor receptor (TNFR) family protein that plays an important role in B cell development. CD154/CD40L is the physiological ligand of CD40. We have determined the crystal structure of the CD40-CD154 complex at 3.5 A resolution. The binding site of CD40 is located in a crevice formed between two CD154 subunits. Charge complementarity plays a critical role in the CD40-CD154 interaction. Some of the missense mutations found in hereditary hyper-IgM syndrome can be mapped to the CD40-CD154 interface. The CD40 interaction area of one of the CD154 subunits is twice as large as that of the other subunit forming the binding crevice. This is because cysteine-rich domain 3 (CRD3) of CD40 has a disulfide bridge in an unusual position that alters the direction of the ladder-like structure of CD40. The Ser(132) loop of CD154 is not involved in CD40 binding but its substitution significantly reduces p38- and ERK-dependent signaling by CD40, whereas JNK-dependent signaling is not affected. These findings suggest that ligand-induced di- or trimerization is necessary but not sufficient for complete activation of CD40.

Crystallographic and mutational analysis of the CD40-CD154 complex and its implications for receptor activation., An HJ, Kim YJ, Song DH, Park BS, Kim HM, Lee JD, Paik SG, Lee JO, Lee H, J Biol Chem. 2011 Apr 1;286(13):11226-35. Epub 2011 Feb 1. PMID:21285457

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Disease

[CD40L_HUMAN] Defects in CD40LG are the cause of X-linked immunodeficiency with hyper-IgM type 1 (HIGM1) [MIM:308230]; also known as X-linked hyper IgM syndrome (XHIM). HIGM1 is an immunoglobulin isotype switch defect characterized by elevated concentrations of serum IgM and decreased amounts of all other isotypes. Affected males present at an early age (usually within the first year of life) recurrent bacterial and opportunistic infections, including Pneumocystis carinii pneumonia and intractable diarrhea due to cryptosporidium infection. Despite substitution treatment with intravenous immunoglobulin, the overall prognosis is rather poor, with a death rate of about 10% before adolescence.[1][2][3][4][5][6][7][8][9][10] [TNR5_HUMAN] Defects in CD40 are the cause of immunodeficiency with hyper-IgM type 3 (HIGM3) [MIM:606843]. A rare immunodeficiency syndrome characterized by normal or elevated serum IgM levels with absence of IgG, IgA, and IgE. It results in a profound susceptibility to bacterial infections.[11]

Function

[CD40L_HUMAN] Mediates B-cell proliferation in the absence of co-stimulus as well as IgE production in the presence of IL-4. Involved in immunoglobulin class switching.[12] Release of soluble CD40L from platelets is partially regulated by GP IIb/IIIa, actin polymerization, and an matrix metalloproteinases (MMP) inhibitor-sensitive pathway.[13] [TNR5_HUMAN] Receptor for TNFSF5/CD40LG.

About this Structure

3qd6 is a 10 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

  • An HJ, Kim YJ, Song DH, Park BS, Kim HM, Lee JD, Paik SG, Lee JO, Lee H. Crystallographic and mutational analysis of the CD40-CD154 complex and its implications for receptor activation. J Biol Chem. 2011 Apr 1;286(13):11226-35. Epub 2011 Feb 1. PMID:21285457 doi:10.1074/jbc.M110.208215
  1. Aruffo A, Farrington M, Hollenbaugh D, Li X, Milatovich A, Nonoyama S, Bajorath J, Grosmaire LS, Stenkamp R, Neubauer M, et al.. The CD40 ligand, gp39, is defective in activated T cells from patients with X-linked hyper-IgM syndrome. Cell. 1993 Jan 29;72(2):291-300. PMID:7678782
  2. Korthauer U, Graf D, Mages HW, Briere F, Padayachee M, Malcolm S, Ugazio AG, Notarangelo LD, Levinsky RJ, Kroczek RA. Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM. Nature. 1993 Feb 11;361(6412):539-41. PMID:7679206 doi:http://dx.doi.org/10.1038/361539a0
  3. DiSanto JP, Bonnefoy JY, Gauchat JF, Fischer A, de Saint Basile G. CD40 ligand mutations in x-linked immunodeficiency with hyper-IgM. Nature. 1993 Feb 11;361(6412):541-3. PMID:8094231 doi:http://dx.doi.org/10.1038/361541a0
  4. Allen RC, Armitage RJ, Conley ME, Rosenblatt H, Jenkins NA, Copeland NG, Bedell MA, Edelhoff S, Disteche CM, Simoneaux DK, et al.. CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome. Science. 1993 Feb 12;259(5097):990-3. PMID:7679801
  5. Macchi P, Villa A, Strina D, Sacco MG, Morali F, Brugnoni D, Giliani S, Mantuano E, Fasth A, Andersson B, et al.. Characterization of nine novel mutations in the CD40 ligand gene in patients with X-linked hyper IgM syndrome of various ancestry. Am J Hum Genet. 1995 Apr;56(4):898-906. PMID:7717401
  6. Saiki O, Tanaka T, Wada Y, Uda H, Inoue A, Katada Y, Izeki M, Iwata M, Nunoi H, Matsuda I, et al.. Signaling through CD40 rescues IgE but not IgG or IgA secretion in X-linked immunodeficiency with hyper-IgM. J Clin Invest. 1995 Feb;95(2):510-4. PMID:7532185 doi:http://dx.doi.org/10.1172/JCI117692
  7. Katz F, Hinshelwood S, Rutland P, Jones A, Kinnon C, Morgan G. Mutation analysis in CD40 ligand deficiency leading to X-linked hypogammaglobulinemia with hyper IgM syndrome. Hum Mutat. 1996;8(3):223-8. PMID:8889581 doi:<223::AID-HUMU5>3.0.CO;2-A 10.1002/(SICI)1098-1004(1996)8:3<223::AID-HUMU5>3.0.CO;2-A
  8. Lin Q, Rohrer J, Allen RC, Larche M, Greene JM, Shigeoka AO, Gatti RA, Derauf DC, Belmont JW, Conley ME. A single strand conformation polymorphism study of CD40 ligand. Efficient mutation analysis and carrier detection for X-linked hyper IgM syndrome. J Clin Invest. 1996 Jan 1;97(1):196-201. PMID:8550833 doi:http://dx.doi.org/10.1172/JCI118389
  9. Nonoyama S, Shimadzu M, Toru H, Seyama K, Nunoi H, Neubauer M, Yata J, Och HD. Mutations of the CD40 ligand gene in 13 Japanese patients with X-linked hyper-IgM syndrome. Hum Genet. 1997 May;99(5):624-7. PMID:9150729
  10. Seyama K, Nonoyama S, Gangsaas I, Hollenbaugh D, Pabst HF, Aruffo A, Ochs HD. Mutations of the CD40 ligand gene and its effect on CD40 ligand expression in patients with X-linked hyper IgM syndrome. Blood. 1998 Oct 1;92(7):2421-34. PMID:9746782
  11. Ferrari S, Giliani S, Insalaco A, Al-Ghonaium A, Soresina AR, Loubser M, Avanzini MA, Marconi M, Badolato R, Ugazio AG, Levy Y, Catalan N, Durandy A, Tbakhi A, Notarangelo LD, Plebani A. Mutations of CD40 gene cause an autosomal recessive form of immunodeficiency with hyper IgM. Proc Natl Acad Sci U S A. 2001 Oct 23;98(22):12614-9. PMID:11675497 doi:10.1073/pnas.221456898
  12. Furman MI, Krueger LA, Linden MD, Barnard MR, Frelinger AL 3rd, Michelson AD. Release of soluble CD40L from platelets is regulated by glycoprotein IIb/IIIa and actin polymerization. J Am Coll Cardiol. 2004 Jun 16;43(12):2319-25. PMID:15193700 doi:10.1016/j.jacc.2003.12.055
  13. Furman MI, Krueger LA, Linden MD, Barnard MR, Frelinger AL 3rd, Michelson AD. Release of soluble CD40L from platelets is regulated by glycoprotein IIb/IIIa and actin polymerization. J Am Coll Cardiol. 2004 Jun 16;43(12):2319-25. PMID:15193700 doi:10.1016/j.jacc.2003.12.055

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