Abstract
BOK is an evolutionarily conserved BCL-2 family member that resembles the apoptotic effectors BAK and BAX in sequence and structure. Based on these similarities, BOK has traditionally been classified as a BAX-like pro-apoptotic protein. However, the mechanism of action and cellular functions of BOK remains controversial. While some studies propose that BOK could replace BAK and BAX to elicit apoptosis, others attribute to this protein an indirect way of apoptosis regulation. Adding to the debate, BOK has been associated with a plethora of non-apoptotic functions that makes this protein unpredictable when dictating cell fate. Here, we compile the current knowledge and open questions about this paradoxical protein with a special focus on its structural features as the key aspect to understand BOK biological functions.
Highlights
The proteins of the BCL-2 family are the main regulators of the intrinsic apoptotic pathway and play a pivotal role in tumorigenic cell removal and cancer treatment effectiveness [1,2,3]
They form a complex interaction network that controls the key step of mitochondrial outer membrane permeabilization (MOMP), which is considered the point of no return in the cell death decision
There are around 20 members in the BCL-2 family, which are typically classified into three groups according to their impact on cell death and the presence of up to four conserved BCL-2 homology (BH) motifs: (i) the pro-apoptotic effectors, including BAK and BAX, and to which BCL2-related ovarian killer (BOK) has been traditionally assigned, contain BH1-BH4 motifs and directly elicit MOMP, (ii) the anti-apoptotic members, which possess all four BH motifs and primarily function by inhibiting MOMP; (iii) the BH3-only proteins, which promote apoptosis either by directly activating the pro-apoptotic effectors and/or by sensitizing to MOMP by blocking the anti-apoptotic members [5,6]
Summary
The proteins of the BCL-2 family are the main regulators of the intrinsic apoptotic pathway and play a pivotal role in tumorigenic cell removal and cancer treatment effectiveness [1,2,3]. There are around 20 members in the BCL-2 family, which are typically classified into three groups according to their impact on cell death and the presence of up to four conserved BCL-2 homology (BH) motifs: (i) the pro-apoptotic effectors, including BAK and BAX, and to which BOK has been traditionally assigned, contain BH1-BH4 motifs and directly elicit MOMP, (ii) the anti-apoptotic members (like BCL-2, BCL-XL, and MCL-1), which possess all four BH motifs and primarily function by inhibiting MOMP; (iii) the BH3-only proteins (like BID, BIM, or BAD), which promote apoptosis either by directly activating the pro-apoptotic effectors and/or by sensitizing to MOMP by blocking the anti-apoptotic members [5,6] Despite their functional divergence, both pro-apoptotic and anti-apoptotic multidomain members fold into a similar globular structure: two central hydrophobic α-helices surrounded by six or seven amphipathic α-helices [7,8]. BOK appears to regulate multiple non-apoptotic processes including mitochondrial dynamics, calcium signaling, and metabolism via poorly understood mechanisms [44,45]
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