Study Reveals Protein Structure of the Human Apoptosome

Did you know that in an adult human, between 50-70 billion cells commit suicide each day? As a result of environmental stress or developmental cues, damaged or unwanted cells undergo “apoptosis” or “programmed cell death,” a process during which these cells are removed in a controlled manner, and the resulting cellular components may be recycled.

Cellular signaling in the programmed death pathway culminates in the formation of a complex assembly of proteins termed the “apoptosome.” This wheel-like structure recruits and activates specific proteases to dismantle proteins in the cytoplasm and the nucleus. Thus, the cell is broken down to pieces from the inside by this “wheel of death.”

A team of investigators led by Christopher W. Akey, PhD, professor of Physiology & Biophysics, determined the first near atomic structure of the active apoptosome. This study, which appears online in the journal eLife , uses state-of-the-art cryo-electron microscopy to build a three-dimensional model of this wheel of death. This model provides a framework to better understand how cell death occurs.

The apoptosome is revealed as a wheel-like complex with seven spokes. On top of the wheel is a spiral-shaped disk that allows for docking and subsequent activation of proteases, which then target cellular components. When active, the apoptosome is revealed to be a dynamic machine with three to five protease molecules tethered to the wheel at any given time. The number of proteolytic units may vary, resulting in a changing level of dismantling activity.

“Apoptosis plays a central role in the maintenance of human health,” explained Akey. “These death pathways provide a line of defense against unrestricted cellular proliferation that occurs in many cancers and may be upregulated in AIDS, neurodegenerative disease, and stroke.” It is hoped that drugs may be found that target this wheel of death to either enhance or suppress its function.

Funding for this study was provided by the National Institute of Health (NIGMS)

Authors are Tat Cheung Cheng, Chuan Hong, Ildiko V. Akey, Shujun Yuan, and Christopher W. Akey. A near atomic structure of the active human apoptosome. eLife 2016.

Submitted by Sherry Yan, MD