Structural basis of BAK sequestration by MCL-1 in apoptosis.

in Molecular cell by Shagun Srivastava, Giridhar Sekar, Adedolapo Ojoawo, Anup Aggarwal, Elisabeth Ferreira, Emiko Uchikawa, Meek Yang, Christy R Grace, Raja Dey, Yi-Lun Lin, Cristina D Guibao, Seetharaman Jayaraman, Somnath Mukherjee, Anthony A Kossiakoff, Bin Dong, Alexander Myasnikov, Tudor Moldoveanu

TLDR

  • A new study reveals the structure of a protein complex involved in apoptosis regulation and highlights the need for better cancer drug targets.
  • The study shows that current MCL-1 inhibitors are inefficient in neutralizing the MCL-1:BAK complex, requiring high doses to initiate apoptosis.
  • Future research is needed to develop superior clinical candidate MCL-1 inhibitors to effectively target the MCL-1:BAK complex in cancer therapy.

Abstract

Apoptosis controls cell fate, ensuring tissue homeostasis and promoting disease when dysregulated. The rate-limiting step in apoptosis is mitochondrial poration by the effector B cell lymphoma 2 (BCL-2) family proteins BAK and BAX, which are activated by initiator BCL-2 homology 3 (BH3)-only proteins (e.g., BIM) and inhibited by guardian BCL-2 family proteins (e.g., MCL-1). We integrated structural, biochemical, and pharmacological approaches to characterize the human prosurvival MCL-1:BAK complex assembled from their BCL-2 globular core domains. We reveal a canonical interaction with BAK BH3 bound to the hydrophobic groove of MCL-1 and disordered and highly dynamic BAK regions outside the complex interface. We predict similar conformations of activated effectors in complex with other guardians or effectors. The MCL-1:BAK complex is a major cancer drug target. We show that MCL-1 inhibitors are inefficient in neutralizing the MCL-1:BAK complex, requiring high doses to initiate apoptosis. Our study underscores the need to design superior clinical candidate MCL-1 inhibitors.

Overview

  • The study focused on understanding the human prosurvival MCL-1:BAK complex, a major cancer drug target, and its role in regulating apoptosis.
  • The researchers used a combination of structural, biochemical, and pharmacological approaches to characterize the complex and its interactions.
  • The study aimed to understand the mechanism of the complex and design superior clinical candidate MCL-1 inhibitors.

Comparative Analysis & Findings

  • The study revealed a canonical interaction between BAK BH3 and the hydrophobic groove of MCL-1, with disordered and dynamic BAK regions outside the complex interface.
  • The researchers found that MCL-1 inhibitors are inefficient in neutralizing the MCL-1:BAK complex, requiring high doses to initiate apoptosis.
  • The study predicts similar conformations of activated effectors in complex with other guardians or effectors.

Implications and Future Directions

  • The study highlights the need to design superior clinical candidate MCL-1 inhibitors to effectively target the MCL-1:BAK complex in cancer therapy.
  • Future research could focus on developing new MCL-1 inhibitors that can effectively neutralize the complex and induce apoptosis in cancer cells.
  • The study's findings could also lead to a better understanding of the mechanisms of apoptosis and the regulation of cell fate in healthy and diseased tissues.
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