Profiling of the Bcl-2/Bcl-XL-binding sites on type 1 IP3 receptor

The trans-membrane domain of Bcl-2α, but not its hydrophobic cleft, is a critical determinant for efficient IP3 receptor inhibition

“…We performed a sequence alignment of the BH3 domains of different Bcl-2 proteins with the fragment of the central modulatory domain of IP 3 R1 (Dom 3), shown in previous studies to bind Bcl-2 [27, 38, 42]. This analysis revealed the presence of a BH3 motif (a.a. 1332-1342) upstream of the previously described region in Dom 3 of IP 3 R targeted by the BH4 domain of Bcl-2 (a.a. 1389-1408) (Figure 1A) [43].…”

“…Nevertheless, the relatively low affinity of inhibition by the BH4 domain (measured in vitro IC 50 =30μM) [27, 39] cannot explain the potent inhibitory effect of Bcl-2 full-length protein in physiological conditions. This Achilles' heel of the model suggests that additional domains in Bcl-2 could be responsible for an efficient in cellulo inhibition of IP 3 R. Interestingly, the C-terminal domain, containing the last 6 th TMD of the IP 3 R (C-term Dom, a.a. 2512-2749), which is in close proximity of the channel pore is also targeted by Bcl-2 [41, 42], but the mechanism and significance of this interaction are not completely solved. The same C-term Dom of IP 3 R also appeared to be responsible for interaction with other members of the family: Bcl-Xl and Mcl-1 [41].…”

The BH4 Domain of Anti-apoptotic Bcl-XL, but Not That of the Related Bcl-2, Limits the Voltage-dependent Anion Channel 1 (VDAC1)-mediated Transfer of Pro-apoptotic Ca2+ Signals to Mitochondria

“…Bcl-2 mainly suppresses pro-apoptotic Ca 2ϩ transients by dampening Ca 2ϩ flux through IP 3 R channels (18), although Bcl-XL promotes pro-survival Ca 2ϩ oscillations by sensitizing IP 3 Rs to low levels of IP 3 signaling (19). These distinct effects of Bcl-2 and Bcl-XL on IP 3 R function reflect differences in the molecular determinants underlying their interaction with the IP 3 R. Bcl-2 through its BH4 domain targets a site located in the center of the modulatory and regulatory domain of the IP 3 R, although Bcl-XL, through a yet unidentified domain, preferentially targets the 6th transmembrane domain located in the proximity of the C-terminal part of the IP 3 R's Ca 2ϩ channel pore (20). We recently found a critical and conserved difference between the BH4 domain of Bcl-2 (Lys-17) and Bcl-XL (Asp-11), being responsible for the privileged binding and inhibition of IP 3 R channels by BH4-Bcl-2 but not by BH4-Bcl-XL (21).…”

Bcl-2 binds to and inhibits ryanodine receptors

“…Therefore, we exploited previously gained insights into the domains of IP 3 Rs and Bcl-2 responsible for IP 3 R-Bcl-2-complex formation (Monaco et al, 2012a;Monaco et al, 2012b;Rong et al, 2009). Fig.…”

“…It has become increasingly clear that Bcl-2 proteins also modulate intracellular Ca 2+ signaling events by directly targeting Ca 2+ transport mechanisms at different cellular locations. At the level of the endoplasmic reticulum (ER), the main intracellular Ca 2+ store, Bcl-2-family members target the inositol 1,4,5-trisphosphate (IP 3 ) receptor (IP 3 R) (Monaco et al, 2012a;Oakes et al, 2005;Rong et al, 2008;White et al, 2005), sarco/endoplasmic-reticulum Ca 2+ -ATPases (SERCAs) (Kuo et al, 1998) and Bax inhibitor 1 (BI-1, also known as TMBIM6) (Ahn et al, 2010;Xu and Reed, 1998). At the mitochondrial outer membranes, Bcl-2 proteins target the voltage-dependent anion channels (VDACs) (Arbel and ShoshanBarmatz, 2010;Arbel et al, 2012;Plötz et al, 2012).…”