Bcl-2 homologous antagonist killer

This article is about the mammalian BAK1 gene. For the plant gene with the same symbol, see BRI1-associated receptor kinase 1.

BCL2-antagonist/killer 1
250px PDB rendering based on 2ims.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1BXL, 2IMS, 2IMT, 2JBY, 2JCN, 2LP8, 2M5B, 2XPX, 2YV6, 3I1H, 3QBR, 4D2L, 4U2U, 4U2V, 5AJK
Identifiers
Symbols	BAK1 ; BAK; BAK-LIKE; BCL2L7; CDN1
External IDs	OMIM: 600516 MGI: 1097161 HomoloGene: 917 ChEMBL: 5609 GeneCards: BAK1 Gene
Gene ontology Molecular function • protein binding • heat shock protein binding • identical protein binding • protein homodimerization activity • metal ion binding • protein heterodimerization activity • chaperone binding • BH domain binding Cellular component • mitochondrion • mitochondrial outer membrane • endoplasmic reticulum • cytosol • integral component of mitochondrial outer membrane • pore complex Biological process • B cell homeostasis • B cell apoptotic process • release of cytochrome c from mitochondria • blood vessel remodeling • myeloid cell homeostasis • B cell negative selection • apoptotic process • activation of signaling protein activity involved in unfolded protein response • brain development • aging • mitochondrial fusion • cell proliferation • negative regulation of cell proliferation • intrinsic apoptotic signaling pathway in response to DNA damage • activation of cysteine-type endopeptidase activity involved in apoptotic process by cytochrome c • response to fungus • response to mycotoxin • response to UV-C • establishment or maintenance of transmembrane electrochemical gradient • response to gamma radiation • positive regulation of calcium ion transport into cytosol • negative regulation of gene expression • programmed cell death • response to organic cyclic compound • cytolysis • endocrine pancreas development • organ regeneration • endoplasmic reticulum calcium ion homeostasis • negative regulation of endoplasmic reticulum calcium ion concentration • negative regulation of peptidyl-serine phosphorylation • cellular response to UV • limb morphogenesis • response to drug • response to hydrogen peroxide • positive regulation of apoptotic process • regulation of protein homodimerization activity • regulation of protein heterodimerization activity • fibroblast apoptotic process • response to ethanol • positive regulation of proteolysis • regulation of mitochondrial membrane permeability • post-embryonic camera-type eye morphogenesis • regulation of cell cycle • regulation of mitochondrial membrane potential • vagina development • intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress • thymocyte apoptotic process • cellular response to mechanical stimulus • positive regulation of release of cytochrome c from mitochondria • apoptotic signaling pathway • extrinsic apoptotic signaling pathway in absence of ligand • intrinsic apoptotic signaling pathway • activation of cysteine-type endopeptidase activity • positive regulation of endoplasmic reticulum unfolded protein response • positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway • apoptotic process involved in patterning of blood vessels • positive regulation of IRE1-mediated unfolded protein response Sources: Amigo / QuickGO
RNA expression pattern
File:PBB GE BAK1 203728 at tn.png
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	578	12018
Ensembl	ENSG00000030110	ENSMUSG00000057789
UniProt	Q16611	O08734
RefSeq (mRNA)	NM_001188	NM_007523
RefSeq (protein)	NP_001179	NP_031549
Location (UCSC)	Chr 6: 33.57 – 33.58 Mb	Chr 17: 27.02 – 27.03 Mb
PubMed search	[1]	[2]

Bcl-2 homologous antagonist/killer is a protein that in humans is encoded by the BAK1 gene on chromosome 6. The protein encoded by this gene belongs to the BCL2 protein family. BCL2 family members form oligomers or heterodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. This protein localizes to mitochondria, and functions to induce apoptosis. It interacts with and accelerates the opening of the mitochondrial voltage-dependent anion channel, which leads to a loss in membrane potential and the release of cytochrome c. This protein also interacts with the tumor suppressor P53 after exposure to cell stress.

Structure

BAK1 is a pro-apoptotic Bcl-2 protein containing four Bcl-2 homology (BH) domains: BH1, BH2, BH3, and BH4. These domains are composed of nine α-helices, with a hydrophobic α-helix core surrounded by amphipathic helices and a transmembrane C-terminal α-helix anchored to the mitochondrial outer membrane (MOM). A hydrophobic groove formed along the C-terminal of α2 to the N-terminal of α5, and some residues from α8, binds the BH3 domain of other BCL-2 proteins in its active form.

Function

As a member of the BCL2 protein family, BAK1 functions as a pro-apoptotic regulator involved in a wide variety of cellular activities. In healthy mammalian cells, BAK1 localizes primarily to the MOM, but remains in an inactive form until stimulated by apoptotic signaling. The inactive form of BAK1 is maintained by the protein’s interactions with VDAC2, Mtx2, and other anti-apoptotic members of the BCL2 protein family. Nonetheless, VDAC2 functions to recruit newly synthesized BAK1 to the mitochondria to carry out apoptosis. Moreover, BAK1 is believed to induce the opening of the mitochondrial voltage-dependent anion channel, leading to release of cytochrome c from the mitochondria. Alternatively, BAK1 itself forms an oligomeric pore, MAC, in the MOM, through which pro-apoptotic factors leak in a process called MOM permeabilization.

Clinical Significance

Generally, the pro-apoptotic function of BAK1 contributes to neurodegenerative and autoimmune diseases when overexpressed and cancers when inhibited. For instance, dysregulation of the BAK gene has been implicated in human gastrointestinal cancers, indicating that the gene plays a part in the pathogenesis of some cancers.

Overview of signal transduction pathways involved in apoptosis.

BAK1 is also involved in the HIV replication pathway, as the virus induces apoptosis in T cells via Casp8p41, which activates BAK to carry out membrane permeabilization, leading to cell death. Consequently, drugs that regulate BAK1 activity present promising treatments for these diseases.

Recently, one study of the role of genetics in abdominal aortic aneurism (AAA) showed that different BAK1 variants can exist in both diseased and non-diseased AA tissues compared to matching blood samples. Given the current paradigm that all cells have the same genomic DNA, BAK1 gene variants in different tissues may be easily explained by the expression of BAK1 gene on chromosome 6 and one its edited copies on chromosome 20.

Interactions

BAK1 has been shown to interact with:

• BCL2-like 1,
• Bcl-2,
• MCL1,
• P53,
• Casp8p41,
• VDAC2,
• Mtx2,
• Mcl-1,
• Bid,
• Bim, and
• Puma.