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.
Keywords:
BCL-2 antagonist killer BAK; BCL-2 family proteins; BCL-2-like protein 11 BIM; BH3 mimetics; BH3-interacting domain death agonist BID; BH3-only initiator; MCL-1 inhibitors; NMR spectroscopy; Phorbol-12-myristate-13-acetate-induced protein 1 NOXA; X-ray crystallography; apoptosis; apoptosis resistance; cryo-electron microscopy; direct BAK activation; induced myeloid leukemia cell differentiation protein MCL-1; mitochondrial outer membrane permeabilization MOMP; mode II MCL-1:BAK sequestration; mode II neutralization; prodeath effector; prosurvival guardian.