LAUSR

By regulating mitochondrial outer membrane permeabilization (MOMP), the rate-limiting event in caspase activation, BCL-2 family proteins are responsible for apoptosis initiation [1]. Most BCL-2 proteins obey canonical rules of mitochondrial apoptosis [2]. These rules define the intricate protein–protein interactions among the different proand anti-apoptotic proteins to dictate cell fate [3]. The BCL-2-related ovarian killer (BOK) is unusual as it does not play by these rules. For instance, unlike the canonical effectors BAK and BAX, BOK does not require direct activation by the BCL-2 homology 3 (BH3)-only proteins, and is not inhibited by anti-apoptotic BCL-2 proteins [4]. Instead, BOK is constantly shredded by the gp78 E3 ligase–proteasome system to which maintain an undetectable its cellular level [4]. Accordingly, BOK’s role in apoptosis has been revealed upon inhibition of BOK degradation or under ER stress [4]. Although BOK has been definitively implicated in mitochondrial apoptosis initiation in the absence of BAK and BAX as a bona fide effector of MOMP [4, 5], another study casted some doubt over BOK’s independence of regulation by BH3-only proteins regulation of MOMP and its ability to permeabilize mitochondria [6]. Nonetheless, that study corroborated BOK’s ability to permeabilize liposomes and suggested a preference of BOK for the negatively charged phospholipid cardiolipin for efficient membrane permeabilization [6]. Given these unresolved matters, we sought to mechanistically probe BOK-mediated initiation of apoptosis based on a comprehensive structure-function analysis [7]. First, we engineered human BOK protein and determined its structure by nuclear magnetic resonance (NMR) to reveal a typical BCL-2 fold with a ligandbinding groove made up of mostly loop structures that anchor the one turn helix α3 to α2 and α4. This is a flexible region exhibiting dynamics detectable by NMR suggesting that it undergoes conformational exchange, or shape shifting (Figure 1). Corroborating our observations, in the recently determined crystal structure of the BCL-2 core of chicken BOK, two BOK monomers observed in the crystal asymmetric unit exhibited distinct conformations in the hydrophobic groove – one resembling that of the NMR structure and another with α3 wound into a 2-turn helix (Figure 1) [8]. With these studies, we now have access to the entire repertoire BCL-2 family folded protein structures. Editorial