Understand how spontaneous activation leads to cell death

Electron micrograph of single human lymphocytes. Credit: Institute Dr. Trish National Cancer

Apoptosis is a process that causes cell death. It can skew in cancerous cells, causing the disease to persist. Scientists at St. Jude Children’s Research Hospital have discovered the structure of BAK, a protein that triggers programmed cell death. They demonstrated how BAK activates automatically, and essentially turns itself on. Understanding how to induce apoptosis could lead to drugs that kill cancer cells. The results were published online today at Nature Communications.

Apoptosis is initiated by proteins, including BAK, that form pores on the mitochondrial membrane. BAK must be turned on to work, but the activation process is brief and elusive. BAK can be operated by either direct activation or automatic activation. Direct activation is a well-studied process in which proteins such as BID and BIM turn on BAK. Spontaneous activation is a poorly understood process in which the active BAK molecule converts to an inactive molecule.

“Our work shows how BAK is automatically activated,” said corresponding author Theodore Moldovino, Ph.D., Departments of Structural Biology and Chemical Biology and Therapeutics at St. Jude. “Once active BAK is produced through direct activation by BID or BIM, which are two primary activators, then the active BAK can function and turn on the inactive BAK.”

Structural changes are the key

The researchers used structural biology, biochemistry and cellular assays to determine the mechanism of BAK self-activation. They have produced the first crystal structure for automatically activated BAK. The structure revealed that conformational changes (shape) destabilize an important inhibitory helix. This instability lies in a common mechanism of BAK activation by BID, BIM and BAK.

The BH3 domain is a ligand already known to be involved in direct activation. The researchers identified positions in the BH3 domain that were beneficial for BAK activation or inhibition. They have identified crystal structures that show how BH3 bonds of high affinity (strong affinity) can activate and inhibit BAK. Ultimately, the work indicates that both direct activation and self-activation processes cooperate to induce apoptosis in cells.

More selective cancer drugs

Efforts for pharmacological apoptosis have largely focused on proteins that act as ‘brakes’ for the process, such as BCL-2 and BCL-XL.

“Our work underscores the need for cancer treatment approaches that remove the brakes but also lead to the formation of pores in apoptosis,” said first author Jitika Singh, PhD, Departments of Structural Biology, Chemical Biology and Therapeutics at St. Jude. “Getting this clearer understanding of the mechanisms of BAK activation may lead to more selective drugs that lead to cell death.”

Other authors of the study are Christina Guibao, Gyaraman Seetharaman, Anup Aggarwal, Kristi Grace, Dan McNamara, Sivaraja Vaithyalingam, M. Brett Waddell of St. Jude.

Results reveal a novel mechanism of ALK activation

more information:
Geetika Singh et al, The structural basis of BAK activation in the initiation of mitochondrial apoptosis, Nature Communications (2022). DOI: 10.1038 / s41467-021-27851-y

Presented by St. Jude Children’s Research Hospital

the quote: Understanding How Autoactivation Leads to Cell Death (2022, January 11) Retrieved on January 15, 2022 from https://phys.org/news/2022-01-autoactivation-triggers-cell-death.html

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