Bcl-2-associated X protein

BCL2-associated X protein
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1F16​, 2G5B​, 2K7W​, 2LR1​, 3PK1​, 3PL7​, 4BD2​, 4BD6​, 4BD7​, 4BD8​, 4BDU​
Identifiers
Symbols	BAX ; BCL2L4
External IDs	OMIM: 600040 MGI: 99702 HomoloGene: 7242 ChEMBL: 5318 GeneCards: BAX Gene
Gene ontology Molecular function • protein binding • lipid binding • channel activity • heat shock protein binding • protein complex binding • identical protein binding • protein homodimerization activity • protein heterodimerization activity • chaperone binding • BH3 domain binding Cellular component • nucleus • nuclear envelope • mitochondrion • mitochondrial outer membrane • mitochondrial permeability transition pore complex • endoplasmic reticulum • endoplasmic reticulum membrane • cytosol • membrane • pore complex • extracellular exosome • Bcl-2 family protein complex • BAX complex Biological process • ovarian follicle development • neuron migration • T cell homeostatic proliferation • B cell homeostasis • B cell apoptotic process • kidney development • release of cytochrome c from mitochondria • protein insertion into mitochondrial membrane involved in apoptotic signaling pathway • blood vessel remodeling • myeloid cell homeostasis • B cell negative selection • B cell homeostatic proliferation • positive regulation of B cell apoptotic process • glycosphingolipid metabolic process • regulation of nitrogen utilization • apoptotic process • activation of cysteine-type endopeptidase activity involved in apoptotic process • transformed cell apoptotic process • activation of signaling protein activity involved in unfolded protein response • inner mitochondrial membrane organization • outer mitochondrial membrane organization • germ cell development • mitochondrial fusion • extrinsic apoptotic signaling pathway via death domain receptors • intrinsic apoptotic signaling pathway in response to DNA damage • activation of cysteine-type endopeptidase activity involved in apoptotic process by cytochrome c • apoptotic mitochondrial changes • fertilization • response to toxic substance • response to salt stress • establishment or maintenance of transmembrane electrochemical gradient • response to gamma radiation • programmed cell death • viral process • hypothalamus development • cerebral cortex development • negative regulation of protein binding • positive regulation of protein oligomerization • endoplasmic reticulum calcium ion homeostasis • negative regulation of endoplasmic reticulum calcium ion concentration • release of matrix enzymes from mitochondria • negative regulation of peptidyl-serine phosphorylation • regulation of mammary gland epithelial cell proliferation • glial cell apoptotic process • cellular response to UV • ectopic germ cell programmed cell death • response to cocaine • odontogenesis of dentin-containing tooth • response to drug • positive regulation of apoptotic process • regulation of protein homodimerization activity • regulation of protein heterodimerization activity • negative regulation of neuron apoptotic process • positive regulation of neuron apoptotic process • mitochondrial fragmentation involved in apoptotic process • development of secondary sexual characteristics • cellular respiration • retinal cell programmed cell death • response to copper ion • positive regulation of developmental pigmentation • negative regulation of fibroblast proliferation • spermatid differentiation • post-embryonic camera-type eye morphogenesis • response to axon injury • homeostasis of number of cells within a tissue • protein oligomerization • protein homooligomerization • positive regulation of release of sequestered calcium ion into cytosol • neuron apoptotic process • response to corticosterone • regulation of cell cycle • regulation of mitochondrial membrane potential • Sertoli cell proliferation • retina development in camera-type eye • positive regulation of apoptotic process involved in mammary gland involution • vagina development • intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress • thymocyte apoptotic process • mitochondrion morphogenesis • intrinsic apoptotic signaling pathway by p53 class mediator • positive regulation of release of cytochrome c from mitochondria • apoptotic signaling pathway • extrinsic apoptotic signaling pathway • extrinsic apoptotic signaling pathway in absence of ligand • intrinsic apoptotic signaling pathway • activation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway • 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 • apoptotic process involved in embryonic digit morphogenesis • regulation of mitochondrial membrane permeability involved in programmed necrotic cell death • positive regulation of apoptotic DNA fragmentation • positive regulation of IRE1-mediated unfolded protein response • retinal cell apoptotic process • B cell receptor apoptotic signaling pathway • negative regulation of apoptotic signaling pathway • positive regulation of extrinsic apoptotic signaling pathway in absence of ligand • positive regulation of intrinsic apoptotic signaling pathway Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	581	12028
Ensembl	ENSG00000087088	ENSMUSG00000003873
UniProt	Q07812	Q07813
RefSeq (mRNA)	NM_001291428	NM_007527
RefSeq (protein)	NP_001278357	NP_031553
Location (UCSC)	Chr 19: 48.95 – 48.96 Mb	Chr 7: 45.46 – 45.47 Mb
PubMed search

Apoptosis regulator BAX, also known as bcl-2-like protein 4, is a protein that in humans is encoded by the BAX gene. BAX is a member of the Bcl-2 gene family. BCL2 family members form hetero- or homodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. This protein forms a heterodimer with BCL2, and functions as an apoptotic activator. This protein is reported to interact with, and increase the opening of, the mitochondrial voltage-dependent anion channel (VDAC), which leads to the loss in membrane potential and the release of cytochrome c. The expression of this gene is regulated by the tumor suppressor P53 and has been shown to be involved in P53-mediated apoptosis.^[1]

Structure

The BAX gene was the first identified pro-apoptotic member of the Bcl-2 protein family.^[2] Bcl-2 family members share one or more of the four characteristic domains of homology entitled the Bcl-2 homology (BH) domains (named BH1, BH2, BH3 and BH4), and can form hetero- or homodimers.^[2][3] 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 BAX or BCL-2 proteins in its active form. In the protein’s inactive form, the groove binds its transmembrane domain, transitioning it from a membrane-bound to a cytosolic protein. A smaller hydrophobic groove formed by the α1 and α6 helices is located on the opposite side of the protein from the major groove, and may serve as a BAX activation site.^[4]

Orthologs of the BAX gene have been identified in most mammals for which complete genome data are available.^[5]

Function

In healthy mammalian cells, the majority of BAX is found in the cytosol, but upon initiation of apoptotic signaling, Bax undergoes a conformational shift. Upon induction of apoptosis, BAX becomes organelle membrane-associated, and in particular, mitochondrial membrane associated.^{[6][7][8][9][10]}

BAX is believed to interact with, and induce the opening of the mitochondrial voltage-dependent anion channel, VDAC.^[11] Alternatively, growing evidence also suggests that activated BAX and/or Bak form an oligomeric pore, MAC in the MOM.^[12] This results in the release of cytochrome c and other pro-apoptotic factors from the mitochondria, often referred to as mitochondrial outer membrane permeabilization, leading to activation of caspases.^[13] This defines a direct role for BAX in mitochondrial outer membrane permeabilization. BAX activation is stimulated by various abiotic factors, including heat, hydrogen peroxide, low or high pH, and mitochondrial membrane remodeling. In addition, it can become activated by binding BCL-2, as well as non-BCL-2 proteins such as p53 and Bif-1. Conversely, BAX can become inactivated by interacting with VDAC2, Pin1, and IBRDC2.^[4]

Clinical Significance

The expression of BAX is upregulated by the tumor suppressor protein p53, and BAX has been shown to be involved in p53-mediated apoptosis. The p53 protein is a transcription factor that, when activated as part of the cell's response to stress, regulates many downstream target genes, including BAX. Wild-type p53 has been demonstrated to upregulate the transcription of a chimeric reporter plasmid utilizing the consensus promoter sequence of BAX approximately 50-fold over mutant p53. Thus it is likely that p53 promotes BAX's apoptotic faculties in vivo as a primary transcription factor. However, p53 also has a transcription-independent role in apoptosis. In particular, p53 interacts with BAX, promoting its activation as well as its insertion into the mitochondrial membrane.^[14][15][16]

Drugs that activate BAX, such as ABT737, a BH3 mimetic, hold promise as anticancer treatments by inducing apoptosis in cancer cells.^[4] For instance, binding of HA-BAD to BCL-xL and concomitant disruption of BAX:BCL-xL interaction was found to partly reverse paclitaxel resistance in human ovarian cancer cells.^[17] Meanwhile, excessive apoptosis in such conditions as ischemia reperfusion injury and amyotrophic lateral sclerosis may benefit from drug inhibitors of BAX.^[4]

Interactions

Overview of signal transduction pathways involved with apoptosis.

Bcl-2-associated X protein has been shown to interact with:

• Bcl-2,^{[2][3][18][19][20]}
• BCL2L1,^{[3][17][21][22]}
• BCL2A1^[3][23]
• SH3GLB1,^[9][24]
• SLC25A4,^[25]
• VDAC1,^[11][13]
• YWHAQ,^[26]
• Bid,^[4]
• Bim,^[4]
• Puma,^[4]
• Noxa,^[4]
• cholesterol,^[27] and
• cardiolipin.^[27]

See also

• Apoptosis
• Apoptosome
• Bcl-2
• BH3 interacting domain death agonist (BID)
• Caspases
• Cytochrome c
• Noxa
• Mitochondrion
• p53 upregulated modulator of apoptosis (PUMA)

References

PDB gallery 1f16: SOLUTION STRUCTURE OF A PRO-APOPTOTIC PROTEIN BAX