Bcl-2 proteins are central regulators of caspase activation, and play a key role in cell death by regulating the integrity of the mitochondrial and endoplasmic reticulum (ER) membranes []. At least 20 Bcl-2 proteins have been reported in mammals, and several others have been identified in viruses. Bcl-2 family proteins fall roughly into three subtypes, which either promote cell survival (anti-apoptotic) or trigger cell death (pro-apoptotic). All members contain at least one of four conserved motifs, termed Bcl-2 Homology (BH) domains. Bcl-2 subfamily proteins, which contain at least BH1 and BH2, promote cell survival by inhibiting the adapters needed for the activation of caspases.Pro-apoptotic members potentially exert their effects by displacing the adapters from the pro-survival proteins; these proteins belong either to the Bax subfamily, which contain BH1-BH3, or to the BH3 subfamily, which mostly only feature BH3 []. Thus, the balance between antagonistic family members is believed to play a role in determining cell fate. Members of the wider Bcl-2 family, which also includes Bcl-x, Bcl-w and Mcl-1, are described by their similarity to Bcl-2 protein, a member of the pro-survival Bcl-2 subfamily []. Full-length Bcl-2 proteins feature all four BH domains, seven α-helices, and a C-terminal hydrophobic motif that targets the protein to the outer mitochondrial membrane, ER and nuclear envelope. BID is a member of the Bcl-2 superfamily of proteins that are key regulators of programmed cell death, hence this family is related to the Apoptosis regulator Bcl-2 protein BH domain. BID is a pro-apoptotic member of the Bcl-2 superfamily and as such posses the ability to target intracellular membranes and contains the BH3 death domain. The activity of BID is regulated by a Caspase 8-mediated cleavage event, exposing the BH3 domain and significantly changing the surface charge and hydrophobicity, which causes a change of cellular localisation [].
This entry is the BID (Bep intracellular delivery) domain located at the C-terminal of Bartonella effector proteins (Beps). It functions as a secretion signal in a subfamily of protein substrates of bacterial type IV secretion (T4S) systems. It mediates transfer of (1) relaxases and the attached DNA during bacterial conjugation, and (2) numerous Beps during protein transfer into host cells infected by pathogenic Bartonella species. Crystal structures of several representative BID domains show a conserved fold characterised by a compact, antiparallel four-helix bundle topped with a hook [].
Pleckstrin homology domain-containing family N member 1 (PLEKHN1), also known as CLPABP, is a cardiolipin phosphatidic acid binding protein that associates with microtubules and accumulates in RNAgranules, which contain cytochrome-c mRNA []. It binds to Bid (a pro-apoptotic protein), removes Bid from transient Bid-Bax complexes, and promotes apoptosis [].
VbhT is a bacterial Fic protein of the mammalian pathogen B. schoenbuchensis. It is composed of an N-terminal FIC domain and a C-terminal BID domain. FIC domains are known to catalyse adenylylation (also called AMPylation). This entry represents VbhA, an antitoxin that binds FIC domain (filamentation induced by cyclic AMP) of VbhT and inhibits its activity. It inhibits the adenylylation activity of VbhT by positioning close to the putative ATP-binding site, hence competing with ATP binding [].
VbhA is the antitoxin to VbhT. VbhT is a toxin of the mammalian pathogen Bartonella schoenbuchensis responsible for the disruptive adenylation of host proteins []. VbhT is composed of an N-terminal FIC domain and a C-terminal BID domain. VbhT also induces FIC-domain-mediated growth arrest in bacteria. It is inhibited by this antitoxin which binds to block the ATP binding site of the VbhT FIC domain []. The antitoxin is related to an N-terminal domain in several Fic family proteins [].
VbhT is a bacterial Fic protein of the mammalian pathogen B. schoenbuchensis. It is composed of an N-terminal FIC domain and a C-terminal BID domain. FIC domains are known to catalyse adenylylation (also called AMPylation). This entry represents VbhA, an antitoxin that binds FIC domain (filamentation induced by cyclic AMP) of VbhT and inhibits its activity. It inhibits the adenylylation activity of VbhT by positioning close to the putative ATP-binding site, hence competing with ATP binding [].Structurally, VbhA consists of 3 alpha helices.
PLEKHN1 (also known as CLPABP) is a cardiolipin phosphatidic acid binding protein that associates with microtubules and accumulates in RNA granules, which contain cytochrome-c mRNA []. It binds to Bid (a pro-apoptotic protein), removes Bid from transient Bid-Bax complexes, and promotes apoptosis []. This entry represents the PH domain of PLEKHN1. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner []. They share little sequence conservation, but all have a commonfold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity []. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane []. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes [].
VDAC-1 (outer mitochondrial membrane protein porin 1) is a voltage dependent anion channel that mediates the flow of metabolites and ions across the outer mitochondrial membrane. VDAC-1 appeares to be a pro-apoptotic protein through oligomerisation []. It is implicated in cell death induction for its ability to interact with BAX, a protein belonging to the BCL-2 protein family. BAX plays a role in apoptosis and mitochondrial function regulation via multiple protein-protein interactions with BCL-2, BAK, BID or other members of the family [, ]. Voltage dependent anion channels (VDACs) or porins by analogy with bacterial porins, are pore-forming proteins associated with mitochondria, although they are also present in the endoplasmic reticulum (ER) []and plasma membrane []. In mammals, three VDAC isoforms have been identified: VDAC1 to 3. They have a very similar predicted structure, consisting of a 19 amphipathic β-strands barrel with an N-terminal α-helix in the central pore [, ]. The channel opening faces both the cytosol and mitochondrial intermembrane space [, ]. They play a major role in cellular energetic metabolism due to its ability to allow the exchange of molecules between the cytosol and the mitochondrial intermembrane space. They may also play a role in cell death. However, several mouse gene knock out studies show that VDACs are dispensable for both MPT (mitochondrial permeability transition) and Bcl-2 family member-driven cell death [, ].
