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The Intrinsic Apoptotic Pathway

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...

Caspases

Caspases

Caspase, a family of cysteine proteases, serve as effectors in apoptosis. The ced3 gene in C.elegans was first identified to be involved in apoptosis. This gene encodes the ced-3 caspase that is similar to the interleukin-1-beta converting enzyme or ICE in mammals. In addition to apoptosis, caspases also function in the inflammatory response. Inflammatory caspases are essential in activating pro-inflammatory cytokines that recruit immune cells and block the replication of pathogens inside cells.

The Extrinsic Apoptotic Pathway

The Extrinsic Apoptotic Pathway

The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...

Cellular Injury V: Apoptosis and Autophagy

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Cells respond to damage and stress through highly coordinated processes that decide whether they survive or undergo controlled self-destruction. Two major pathways involved in this regulation are apoptosis, a type of programmed cell death, and autophagy, a survival mechanism that helps cells adapt to adverse conditions.ApoptosisApoptosis removes aged or injured cells to maintain tissue balance. During this process, the cell shrinks, chromatin condenses and fragments, and membrane-bound...

Apoptosis

Apoptosis

Apoptosis is a combination of two Greek words, 'apo' and 'ptosis,' meaning separation and falling off, respectively. Hippocrates used this word to describe gangrene, which was caused due to bandaging of fractured bones. Apoptosis was distinguished from necrosis in 1970 when John Kerr reported observations of morphological changes occurring during apoptosis. During one experiment, he observed that the disruption of blood supply to the liver tissue resulted in a size reduction of the tissue.

Phagocytosis of Apoptotic Cells

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Cells undergoing apoptosis form apoptotic bodies that must be removed immediately to prevent inflammation, autoimmune diseases, and necrosis. Phagocytosis is carried out by professional phagocytes such as macrophages or immature dendritic cells. Non-professional phagocytes such as epithelial cells and fibroblasts also take part in this process; however, they are not as effective as professional phagocytes.
Normal cells contain receptors that prevent them from being recognized by phagocytes.

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Related Experiment Video

Updated: May 12, 2026

Examining BCL-2 Family Function with Large Unilamellar Vesicles

Examining BCL-2 Family Function with Large Unilamellar Vesicles

Published on: October 5, 2012

BID-induced structural changes in BAK promote apoptosis.

Tudor Moldoveanu¹, Christy R Grace, Fabien Llambi

¹Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

Nature Structural & Molecular Biology

|April 23, 2013

Summary

The BID protein activates BAK, a key player in apoptosis, by binding to its groove. This interaction initiates a

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Area of Science:

Molecular Biology
Cell Biology
Biochemistry

Background:

The BCL-2-family protein BAK mediates mitochondrial outer-membrane permeabilization (MOMP), a critical step in apoptosis.
The BH3-only protein BID is known to activate BAK for MOMP induction.

Purpose of the Study:

To elucidate the structural basis of BID-mediated BAK activation.
To understand the mechanism of BAK activation by BH3-only proteins.

Main Methods:

Nuclear Magnetic Resonance (NMR) spectroscopy was used to determine the solution structure of the human BID BH3-BAK complex.
Site-directed mutagenesis of BAK (BH1 and BH3 domains) and BID was performed to assess functional consequences.

Main Results:

The structure revealed that BID binds to the canonical BH3-binding groove of BAK, identifying the activation site.
Mutations in BAK's BH1 domain within the groove abolished BID-induced activation and MOMP, while preserving BID binding.
Mutations in BAK's BH3 domain permitted BID binding and activation but impaired BAK oligomerization and MOMP, suggesting a 'hit-and-run' mechanism.
BID dissociates after initial binding, allowing BAK oligomerization at a separate interface for MOMP.
Other BH3-only proteins, NOXA and BAD, are predicted to interact differently and are not direct BAK activators.

Conclusions:

BID activates BAK through a 'hit-and-run' mechanism involving initial binding to the BH3-groove, followed by dissociation to enable BAK oligomerization and MOMP.
The findings clarify the distinct roles of different BH3-only proteins in regulating BAK-mediated apoptosis and provide structural insights into early activation events.