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6e27

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Revision as of 12:46, 7 November 2018

The CARD9 CARD domain-swapped dimer with a zinc ion bound to one of the two zinc binding sites

Structural highlights

6e27 is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	CARD9 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[CARD9_HUMAN] Chronic mucocutaneous candidosis;Deep dermatophytosis. The disease is caused by mutations affecting the gene represented in this entry. Defects induce reduced numbers of CD4(+) Th17 lymphocytes as well as a lack of monocyte-derived cytokines in response to Candida strains. Neutrophils show a selective Candida albicans killing defect with abnormal ultrastructural phagolysosomes and outgrowth of hyphae (PubMed:23335372).^[1]

Function

[CARD9_HUMAN] Adapter protein that plays a key role in innate immune response to a number of intracellular pathogens, such as C.albicans and L.monocytogenes. Is at the crossroads of ITAM-tyrosine kinase and the Toll-like receptors (TLR) and NOD2 signaling pathways. Probably controls various innate immune response pathways depending on the intracellular pathogen. In response to L.monocytogenes infection, acts by connecting NOD2 recognition of peptidoglycan to downstream activation of MAP kinases (MAPK) without activating NF-kappa-B. Also involved in activation of myeloid cells via classical ITAM-associated receptors and TLR: required for TLR-mediated activation of MAPK, while it is not required for TLR-induced activation of NF-kappa-B (By similarity). Controls CLEC7A (dectin-1)-mediated myeloid cell activation induced by the yeast cell wall component zymosan, leading to cytokine production and innate anti-fungal immunity: acts by regulating BCL10-MALT1-mediated NF-kappa-B activation pathway. Activates NF-kappa-B via BCL10. In response to the hyphal form of C.albicans, mediates CLEC6A (dectin-2)-induced I-kappa-B kinase ubiquitination, leading to NF-kappa-B activation via interaction with BCL10. In response to fungal infection, may be required for the development and subsequent differentiation of interleukin 17-producing T helper (TH-17) cells.^[2]

Publication Abstract from PubMed

The caspase recruitment domain-containing protein 9 (CARD9):B-cell lymphoma/leukemia 10 (Bcl10) signaling axis is activated in myeloid cells during the innate immune response to a variety of diverse pathogens. This signaling pathway requires a critical caspase recruitment domain (CARD):CARD interaction between CARD9 and Bcl10 that promotes downstream activation of factors including NF-kappaB and the mitogen-activated protein kinase (MAPK) p38. Despite these insights, CARD9 remains structurally uncharacterized, and little mechanistic understanding of its regulation exists. We unexpectedly found here that the CARD in CARD9 binds to Zn(2+) with picomolar affinity-a concentration comparable to the levels of readily accessible Zn(2+) in the cytosol. NMR solution structures of the CARD9 CARD in the apo and Zn(2+)-bound states revealed that Zn(2+) has little effect on the ground-state structure of the CARD; yet the stability of the domain increased considerably upon Zn(2+) binding, with a concomitant reduction in conformational flexibility. Moreover, Zn(2+) binding inhibited polymerization of the CARD9 CARD into helical assemblies. Here we also present a 20-A resolution negative-stain EM (NS-EM) structure of these filamentous assemblies and show that they adopt a similar helical symmetry as previously reported for filaments of the Bcl10 CARD. Using both bulk assays and direct NS-EM visualization, we further show that the CARD9-CARD assemblies can directly template and thereby nucleate Bcl10 polymerization, a capacity considered critical to propagation of the CARD9:Bcl10 signaling cascade. Our findings indicate that CARD9 is a potential target of Zn(2+)-mediated signaling that affects Bcl10 polymerization in innate immune responses.

Picomolar zinc binding modulates formation of Bcl10-nucleating assemblies of the caspase recruitment domain (CARD) of CARD9.,Holliday MJ, Ferrao R, de Leon Boenig G, Estevez A, Helgason E, Rohou A, Dueber EC, Fairbrother WJ J Biol Chem. 2018 Sep 11. pii: RA118.004821. doi: 10.1074/jbc.RA118.004821. PMID:30206119^[3]

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

References

↑ Drewniak A, Gazendam RP, Tool AT, van Houdt M, Jansen MH, van Hamme JL, van Leeuwen EM, Roos D, Scalais E, de Beaufort C, Janssen H, van den Berg TK, Kuijpers TW. Invasive fungal infection and impaired neutrophil killing in human CARD9 deficiency. Blood. 2013 Mar 28;121(13):2385-92. doi: 10.1182/blood-2012-08-450551. Epub 2013 , Jan 18. PMID:23335372 doi:http://dx.doi.org/10.1182/blood-2012-08-450551
↑ Bertin J, Guo Y, Wang L, Srinivasula SM, Jacobson MD, Poyet JL, Merriam S, Du MQ, Dyer MJ, Robison KE, DiStefano PS, Alnemri ES. CARD9 is a novel caspase recruitment domain-containing protein that interacts with BCL10/CLAP and activates NF-kappa B. J Biol Chem. 2000 Dec 29;275(52):41082-6. PMID:11053425 doi:http://dx.doi.org/10.1074/jbc.C000726200
↑ Holliday MJ, Ferrao R, de Leon Boenig G, Estevez A, Helgason E, Rohou A, Dueber EC, Fairbrother WJ. Picomolar zinc binding modulates formation of Bcl10-nucleating assemblies of the caspase recruitment domain (CARD) of CARD9. J Biol Chem. 2018 Sep 11. pii: RA118.004821. doi: 10.1074/jbc.RA118.004821. PMID:30206119 doi:http://dx.doi.org/10.1074/jbc.RA118.004821

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6e27"

@@ Line 3: / Line 3: @@
 <StructureSection load='6e27' size='340' side='right' caption='[[6e27]], [[Resolution|resolution]] 1.81&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6e27]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6E27 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6E27 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6e27]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6E27 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6E27 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CARD9 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6e27 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6e27 OCA], [http://pdbe.org/6e27 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6e27 RCSB], [http://www.ebi.ac.uk/pdbsum/6e27 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6e27 ProSAT]</span></td></tr>
 </table>
@@ Line 24: / Line 25: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Boenig, G]]
 [[Category: Deuber, E C]]

6e27

From Proteopedia

Revision as of 12:46, 7 November 2018

The CARD9 CARD domain-swapped dimer with a zinc ion bound to one of the two zinc binding sites

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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