Bax

What is BAX Protein?

BAX gene (BCL2 associated X, apoptosis regulator) is a protein coding gene which situated on the long arm of chromosome 19 at locus 19q13. The protein encoded by this gene belongs to the BCL2 protein 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 BAX protein is consisted of 192 amino acids and BAX molecular weight is approximately 21.2 kDa.

What is the Function of BAX Protein?

The BAX protein is usually present as a monomer in the cytoplasm, but upon receiving the apoptotic signal, it transfers to the mitochondria and oligomerizes there, forming pores and resulting in increased permeability of the mitochondrial outer membrane. Activation of the BAX protein involves significant changes in its molecular structure. In the unactivated state, the N-terminal and C-terminal regions of BAX have self-inhibitory properties, maintaining their latent state in the cytoplasm. However, when cells receive apoptotic signals such as the BH3-only protein, BAX undergoes conformational changes that cause the release of its C-terminal helix (α9) and BH3 helix, which promotes its transfer to the mitochondria and oligomerization. In addition, BAX activity is tightly regulated by other members of the BCL-2 family within the cell.

Fig1. Activation of Bax during apoptosis is controlled by lipids at multiple levels. (V Mignard, 2014)

BAX Related Signaling Pathway

As a proapoptotic protein in the Bcl-2 family, BAX interacts with anti-apoptotic proteins such as Bcl-2 and Bcl-xL to control mitochondrial permeability and thereby regulate apoptosis. The accumulation of BAX on the mitochondrial membrane leads to the increase of membrane permeability and the release of cytochrome C, which then binds with APAF-1 to activate Caspase-9 and initiate the caspase cascade, leading to apoptosis. BAX undergoes conformational change and activation under the stimulation of apoptosis signal, and forms oligomers on mitochondria together with Bak protein, resulting in mitochondrial membrane permeation. The serine 184 site of BAX protein can be phosphorylated by different kinases, such as AKT and PKCζ, which affect its pro-apoptotic activity.

BAX Related Diseases

BAX, as a pro-apoptotic protein, plays an important role in tumor development, and its expression level is associated with the survival and death of tumor cells. Abnormal functioning of BAX may affect the normal regulation of the immune system, leading to the development of autoimmune diseases. In neurodegenerative diseases, abnormal activation of BAX may lead to the loss of neurons, which can affect the development of the disease. BAX plays a role in mitochondria-mediated cardiomyocyte apoptosis, and its dysfunction may be related to the pathogenesis of heart failure. The regulatory mechanism and drug discovery of BAX are the focus of current research, aiming to develop small molecule apoptosis regulators targeting BAX and provide new strategies for the treatment of related diseases.

Bioapplications of BAX

The dysfunction of BAX is closely related to the occurrence and development of tumors. Small molecule apoptosis regulators targeting BAX provide a new strategy for cancer therapy and contribute to the development of the next generation of apoptosis regulators. The role of BAX in neurodegenerative diseases is the focus of current research, and by studying BAX antibodies, its relationship with nerve cell death can be explored, providing new perspectives for the treatment of related diseases. BAX is an important target for directly targeted drug discovery, and research has focused on identifying functional and potentially drug-binding sites on BAX, as well as developing small molecule compounds capable of regulating BAX activity. In the treatment of hemophilia, clinical trials of BAX 335 gene therapy have shown its potential in boosting FIX activity and improving symptoms in patients, despite some immune response challenges.