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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...

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...

Anaphase Promoting Complex

Anaphase Promoting Complex

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Mechanism of Filopodia Formation

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Caspases

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Related Experiment Video

Updated: May 13, 2026

Lighting Up the Pathways to Caspase Activation Using Bimolecular Fluorescence Complementation

Lighting Up the Pathways to Caspase Activation Using Bimolecular Fluorescence Complementation

Published on: March 5, 2018

Changes in Apaf-1 conformation that drive apoptosome assembly.

Shujun Yuan¹, Maya Topf, Thomas F Reubold

¹Department of Physiology and Biophysics, Boston University School of Medicine, 700 Albany Street, Boston, MA 02118, USA.

|March 26, 2013

Summary

The apoptosome model reveals how Apaf-1 changes shape to bind cytochrome c and assemble, initiating programmed cell death. This clarifies the intrinsic cell death pathway.

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Area of Science:

Molecular Biology
Cell Biology
Structural Biology

Background:

Apoptosome assembly is a critical, regulated step in the intrinsic pathway of programmed cell death.
Understanding Apaf-1 conformational changes is key to elucidating apoptosome formation.

Purpose of the Study:

To create an improved structural model of the human apoptosome.
To investigate the conformational dynamics of Apaf-1 during apoptosome assembly.

Main Methods:

Utilized a crystal structure of full-length Apaf-1.
Incorporated a single-particle electron density map (~9.5 Å resolution).
Compared Apaf-1 structures in monomeric and assembled apoptosome states.

Main Results:

Developed a detailed human apoptosome model including Apaf-1, beta-propellers, and cytochrome c.
Identified induced-fit binding of cytochrome c to Apaf-1 beta-propellers.
Observed significant conformational changes in Apaf-1, including nucleotide binding module rotation, driving assembly.
Found that Apaf-1 CARD domains may interact with procaspase-9 CARD during or before assembly.

Conclusions:

The improved model elucidates key conformational changes in Apaf-1 that drive apoptosome assembly.
Cytochrome c binding and nucleotide exchange induce significant Apaf-1 structural rearrangements.
Apaf-1 CARD domains are accessible for procaspase-9 interaction, facilitating downstream caspase activation and cell death.