BinCARD

CARD19
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4DWN, 4FH0
Identifiers
Aliases	CARD19 , BinCARD, bA370F5.1, C9orf89, caspase recruitment domain family member 19
External IDs	OMIM: 617726; MGI: 1915730; HomoloGene: 12269; GeneCards: CARD19; OMA:CARD19 - orthologs
Gene location (Human) Chr. Chromosome 9 (human) [1] Band 9q22.31 Start 93,096,217 bp [1] End 93,113,283 bp [1]
Gene location (Mouse) Chr. Chromosome 13 (mouse) [2] Band 13|13 A5 Start 49,356,426 bp [2] End 49,369,513 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in monocyte granulocyte right coronary artery ascending aorta right hemisphere of cerebellum tibial arteries Descending thoracic aorta olfactory zone of nasal mucosa left uterine tube nasal epithelium Top expressed in granulocyte muscle of thigh lip digastric muscle triceps brachii muscle temporal muscle sternocleidomastoid muscle lumbar spinal ganglion right ventricle yolk sac More reference expression data BioGPS n/a
Gene ontology Molecular function CARD domain binding protein binding Cellular component endoplasmic reticulum membrane cytosol nucleus membrane integral component of membrane mitochondrial membranes endoplasmic reticulum mitochondrion Biological process negative regulation of I-kappaB kinase/NF-kappaB signaling Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 84270 68480 Ensembl ENSG00000165233 ENSMUSG00000037960 UniProt Q96LW7 Q9D1I2 RefSeq (mRNA) NM_032310 NM_001318010 NM_001318011 NM_026738 RefSeq (protein) NP_001304939 NP_001304940 NP_115686 NP_081014 Location (UCSC) Chr 9: 93.1 – 93.11 Mb Chr 13: 49.36 – 49.37 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Bcl10-interacting CARD protein, also known as BinCARD, is a protein that in humans is encoded by the C9orf89 gene on chromosome 9. ^{[5] [6]} BinCARD is a member of the death-domain superfamily and contains a caspase recruitment domain (CARD). ^[7] This protein regulates apoptosis and the immune response by inhibiting Bcl10, thus implicating it in diseases stemming from Bcl10 dysfunction. ^{[7] [8]}

Structure

BinCARD, as a CARD-containing protein, is a member of the death-domain superfamily, which shares a six—helix bundle. ^[7] In humans, the protein has two alternatively spliced isoforms: BinCARD-1 and BinCARD-2. Both isoforms share identical sequences until residue 101, which include the CARD domain and exons 1 to 3. The longer isoform, BinCARD-1, has an extended exon 3, while the shorter BinCARD-2 has an extra transmembrane domain. ^[7] The conserved CARD domain has three cysteines in its native form: Cys7, Cys77, and Cys63, of which Cys7 and Cys77 form a disulfide bond and Cys63 becomes a cysteine sulfenic acid when oxidized. ^{[7] [8]}

Function

The BinCARD protein is a member of the death-domain superfamily, which is known for regulating apoptosis and the immune response. ^[7] BinCARD is a negative regulator that binds to, and thus blocks the phosphorylation of, Bcl10, effectively inhibiting Bcl10 from activating the nuclear factor-κB (NF-κB). ^{[7] [8]} In particular, the BinCARD-1 isoform contains an extended C-terminal that has been observed to bind Bcl10, though it mostly localizes to the nucleus. ^{[7] [8]} The second isoform, BinCARD-2, is more abundantly expressed and localizes to both the ER and the mitochondria. This isoform is expected to contribute to apoptosis via redox processes, as its three modifiable cysteines can be oxidized by reactive oxygen species (ROS) to stimulate an innate immune response. ^[8]

Clinical significance

Mutations in BinCARD and other proteins containing CARD domains are linked to Bcl10-related diseases, including lymphoma of mucosa-associated lymphoid tissue. ^[8] Bcl10 has been shown to induce apoptosis and to activate NF-kappaB. This protein is reported to interact with other CARD domain containing proteins including CARD9, 10, 11 and 14, which are thought to function as upstream regulators in NF-kappaB signaling. Accordingly, BinCARD protein has a pivotal role in regulating apoptotic functions.^{[ citation needed ]}

Because of its important biological and physiological functions, apoptosis is pivotal in many clinical constituents. During normal embryologic processes, or during cell injury (such as ischemia-reperfusion injury during heart attacks and strokes) or during developments and processes in cancer, an apoptotic cell undergoes structural changes including cell shrinkage, plasma membrane blebbing, nuclear condensation, and fragmentation of the DNA and nucleus. This is followed by fragmentation into apoptotic bodies that are quickly removed by phagocytes, thereby preventing an inflammatory response. ^[9] It is a mode of cell death defined by characteristic morphological, biochemical and molecular changes. It was first described as a "shrinkage necrosis", and then this term was replaced by apoptosis to emphasize its role opposite mitosis in tissue kinetics. In later stages of apoptosis the entire cell becomes fragmented, forming a number of plasma membrane-bounded apoptotic bodies which contain nuclear and or cytoplasmic elements. The ultrastructural appearance of necrosis is quite different, the main features being mitochondrial swelling, plasma membrane breakdown and cellular disintegration. Apoptosis occurs in many physiological and pathological processes. It plays an important role during embryonal development as programmed cell death and accompanies a variety of normal involutional processes in which it serves as a mechanism to remove "unwanted" cells.^{[ citation needed ]}

BinCARD has reportedly suppressed NF-kappa B activation induced by BCL10 hereby decreasing the amounts of phosphorylated Bcl10. Subsequently, mutations at the residue Leu17 or Leu65, which is highly conserved in CARD, abolished the inhibitory effects of BinCARD on both Bcl10-induced activation of NF-kappa B and phosphorylation of Bcl10. Further, expression of BinCARD inhibited Bcl10 phosphorylation induced by T cell activation signal. These results suggest that BinCARD interacts with Bcl10 to inhibit Bcl10-mediated activation of NF-kappa B and to suppress Bcl10 phosphorylation. ^[8] Accordingly, these processes regulating apoptosis during clinical processes such as cancer and ischemia-reperfusion injury.^{[ citation needed ]}

Interactions

BinCARD has been shown to interact with:

• Bcl10 ^[8]

References

1. GRCh38: Ensembl release 89: ENSG00000165233 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000037960 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. UniProt: Q96LW7
6. "Entrez Gene: chromosome 9 open reading frame 89".
7. Chen KE, Richards AA, Caradoc-Davies TT, Vajjhala PR, Robin G, Lua LH, Hill JM, Schroder K, Sweet MJ, Kellie S, Kobe B, Martin J (May 2013). "The structure of the caspase recruitment domain of BinCARD reveals that all three cysteines can be oxidized" (PDF). Acta Crystallographica Section D. 69 (Pt 5): 774–84. doi:10.1107/S0907444913001558. hdl: 10072/171950 . PMID   23633586.
8. Woo HN, Hong GS, Jun JI, Cho DH, Choi HW, Lee HJ, Chung CW, Kim IK, Jo DG, Pyo JO, Bertin J, Jung YK (Dec 2004). "Inhibition of Bcl10-mediated activation of NF-kappa B by BinCARD, a Bcl10-interacting CARD protein". FEBS Letters. 578 (3): 239–44. doi:10.1016/j.febslet.2004.10.094. PMID   15637807. S2CID   84325562.
9. Kerr JF, Wyllie AH, Currie AR (Aug 1972). "Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics". British Journal of Cancer. 26 (4): 239–57. doi:10.1038/bjc.1972.33. PMC   2008650 . PMID   4561027.

External links

• Human CARD19 genome location and CARD19 gene details page in the UCSC Genome Browser .