RTL10 (Protein Bop; also BOP, C22orf29) is a eutherian gene (22q11.21) domesticated from a Ty3/gypsy sushi-ichi-related LTR retrotransposon and built on a retroviral Gag capsid-like scaffold. Uniquely among the RTL/SIRH family it carries a functional BH3 motif (residues 114-128, with essential Leu118 and Asp123) and behaves as a pro-apoptotic BH3-only member of the Bcl-2 protein family. The 364-residue protein localizes mainly to mitochondria and uses its BH3 helix to engage the voltage-dependent anion channel VDAC1 at the outer mitochondrial membrane and to bind pro-survival Bcl-2 family members (BCL2, BCL-XL, MCL1, BCL2A1, BCL2L2), which sequester it. Whether it is a direct activator of the effectors BAX and BAK or acts only by de-repressing them is not resolved. Purified Bop induces loss of mitochondrial transmembrane potential and release of cytochrome c, and it is partially required for vincristine-induced apoptosis, acting through the intrinsic (mitochondrial) apoptotic pathway. RTL10 has no mouse ortholog, and its protein-coding capacity is retained only in a subset of mammalian lineages.
Definition: Binding to a pro-survival BCL2-family protein through a BH3-mediated interaction to inhibit that protein from sequestering pro-apoptotic BCL2-family effectors or activators.
Justification: RTL10/Bop is a BH3-only protein that donates its BH3 helix to the grooves of pro-survival BCL2-family members (BCL2, BCL-XL, MCL1, A1, BCL-w). GO:0051434 BH3 domain binding annotates the groove-side pro-survival receptor and is directionally wrong for the BH3-only ligand; GO:0046982 protein heterodimerization activity is near-uninformative. The same term was proposed in the BCL2L11 and BID reviews.
Parent term: molecular function inhibitor activity
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:23055042 Human Bop is a novel BH3-only member of the Bcl-2 protein fa... | MODIFY | Summary: RTL10/Bop uses its BH3 domain to contact the loop regions of the voltage-dependent anion channel VDAC1 at the outer mitochondrial membrane. Reason: Bare protein binding is uninformative, but the interaction is characterised: RTL10/Bop contacts VDAC1, an outer-mitochondrial-membrane transporter, through its BH3 domain. GO:0044325 transmembrane transporter binding is the informative binding term for this partner. Proposed replacements: transmembrane transporter binding Supporting Evidence: PMID:23055042 used its BH3 domain to contact the loop regions of voltage dependent anion channel 1 (VDAC1) in the outer mitochondrial membrane |
| GO:0005515 protein binding | IPI PMID:23055042 Human Bop is a novel BH3-only member of the Bcl-2 protein fa... | REMOVE | Summary: RTL10/Bop is proposed to act via the effectors BAX and BAK. Reason: Bare protein binding, removed under the protein-binding policy. The cited text does not demonstrate a direct RTL10/Bop-BAX contact; it states only that Bop "might need to function through Bak and Bax, likely by releasing Bak from Bcl-X(L) sequestration", i.e. an indirect route captured by the pro-survival inhibitor rows. No direct-activator function is shown, so no specific binding MF is asserted here. |
| GO:0005515 protein binding | IPI PMID:23055042 Human Bop is a novel BH3-only member of the Bcl-2 protein fa... | MODIFY | Summary: RTL10/Bop uses its BH3 domain to bind the pro-survival protein BCL-XL (BCL2L1). Reason: Replace uninformative protein binding with the BH3-only-side molecular function: RTL10/Bop donates its BH3 helix to the groove of a pro-survival Bcl-2 family member, the same directional relationship for which the BCL2L11/BID reviews proposed a dedicated term. GO:0046982 protein heterodimerization activity is barely more informative than protein binding and does not capture direction. Proposed replacements: pro-survival BCL2 family protein inhibitor activity Supporting Evidence: PMID:23055042 used its BH3 domain to contact pro-survival Bcl-2 family members (Bcl-2, Bcl-X(L), Mcl-1, A1 and Bcl-w) |
| GO:0005515 protein binding | IPI PMID:23055042 Human Bop is a novel BH3-only member of the Bcl-2 protein fa... | MODIFY | Summary: RTL10/Bop uses its BH3 domain to bind the pro-survival protein MCL1. Reason: Replace uninformative protein binding with the BH3-only-side molecular function: RTL10/Bop donates its BH3 helix to the groove of a pro-survival Bcl-2 family member, as the BCL2L11/BID reviews established. GO:0046982 protein heterodimerization activity does not capture direction. Proposed replacements: pro-survival BCL2 family protein inhibitor activity Supporting Evidence: PMID:23055042 used its BH3 domain to contact pro-survival Bcl-2 family members (Bcl-2, Bcl-X(L), Mcl-1, A1 and Bcl-w) |
| GO:0005515 protein binding | IPI PMID:23055042 Human Bop is a novel BH3-only member of the Bcl-2 protein fa... | REMOVE | Summary: RTL10/Bop is proposed to act via the effectors BAK and BAX. Reason: Bare protein binding, removed under the protein-binding policy. The cited text does not demonstrate a direct RTL10/Bop-BAK contact; it states only that Bop "might need to function through Bak and Bax, likely by releasing Bak from Bcl-X(L) sequestration", i.e. an indirect route captured by the pro-survival inhibitor rows. No direct-activator function is shown, so no specific binding MF is asserted here. |
| GO:0005515 protein binding | IPI PMID:23055042 Human Bop is a novel BH3-only member of the Bcl-2 protein fa... | MODIFY | Summary: RTL10/Bop uses its BH3 domain to bind the pro-survival protein BCL-w (BCL2L2). Reason: Replace uninformative protein binding with the BH3-only-side molecular function: RTL10/Bop donates its BH3 helix to the groove of a pro-survival Bcl-2 family member, as the BCL2L11/BID reviews established. GO:0046982 protein heterodimerization activity does not capture direction. Proposed replacements: pro-survival BCL2 family protein inhibitor activity Supporting Evidence: PMID:23055042 used its BH3 domain to contact pro-survival Bcl-2 family members (Bcl-2, Bcl-X(L), Mcl-1, A1 and Bcl-w) |
| GO:0005515 protein binding | IPI PMID:27107012 Pooled-matrix protein interaction screens using Barcode Fusi... | REMOVE | Summary: High-throughput (barcode-fusion-genetics) interaction with GPRASP2 (Q96D09); no function. Reason: Bare protein binding, removed under the protein-binding policy; high-throughput screen with no functional interpretation, unrelated to the BH3/apoptosis mechanism. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: High-throughput interactome interaction with GPRASP2 (Q96D09); no function. Reason: Bare protein binding, removed under the protein-binding policy; proteome-scale screen with no functional interpretation. |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) inference of mitochondrial localization, consistent with the experimental localization of Bop to mitochondria. Reason: The IBA agrees with the direct experimental evidence that Bop localizes mainly to mitochondria, where it acts at the outer membrane. The target's own experimental annotation is among the IBD evidences, which is expected. Accepted. Supporting Evidence: PMID:23055042 Bop mainly localized to mitochondria |
| GO:0005739 mitochondrion | IDA PMID:23055042 Human Bop is a novel BH3-only member of the Bcl-2 protein fa... | ACCEPT | Summary: Bop mainly localizes to mitochondria, where it acts at the outer membrane via VDAC1 to drive intrinsic apoptosis. Reason: Direct experimental localization. The functional site is specifically the outer mitochondrial membrane (VDAC1 engagement), captured in the core function; the general mitochondrion term is the supported localization and is retained. Supporting Evidence: PMID:23055042 Bop mainly localized to mitochondria |
| GO:0005739 mitochondrion | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping to mitochondrion. Reason: Consistent with the experimental and phylogenetic mitochondrial localization. Accepted. Supporting Evidence: PMID:23055042 Bop mainly localized to mitochondria |
| GO:0051881 regulation of mitochondrial membrane potential | IMP PMID:23055042 Human Bop is a novel BH3-only member of the Bcl-2 protein fa... | ACCEPT | Summary: Purified Bop induces loss of mitochondrial transmembrane potential, and Bop is partially required for vincristine-induced cell death. Reason: Experimental (IMP) evidence: Bop itself causes the change in mitochondrial membrane potential as part of its intrinsic pro-apoptotic activity, so it participates in the process. Accepted. Supporting Evidence: PMID:23055042 purified Bop protein induced the loss of mitochondrial transmembrane potential (ΞΟm) and the release of cytochrome c |
| GO:0097345 mitochondrial outer membrane permeabilization | IMP PMID:23055042 Human Bop is a novel BH3-only member of the Bcl-2 protein fa... | ACCEPT | Summary: Purified Bop induces release of cytochrome c (a hallmark output of mitochondrial outer membrane permeabilization), acting through BAK/BAX at the outer membrane. Reason: Experimental (IMP) evidence: purified Bop drives MOMP (cytochrome c release, ΞΟm loss) via its BH3 helix, engaging VDAC1; whether it activates the BAK/BAX effectors directly or acts by de-repression is unresolved, but it participates in the process directly. Accepted as a core function. Supporting Evidence: PMID:23055042 purified Bop protein induced the loss of mitochondrial transmembrane potential (ΞΟm) and the release of cytochrome c |
| GO:2001244 positive regulation of intrinsic apoptotic signaling pathway | IMP PMID:23055042 Human Bop is a novel BH3-only member of the Bcl-2 protein fa... | NEW | Summary: Bop induces apoptosis in a BH3-domain-dependent manner (Leu118 and Asp123 required), is inhibited by pro-survival Bcl-2 proteins, and is partially required for vincristine-induced death, acting through the intrinsic pathway. Reason: Bop is itself a BH3-only pro-apoptotic effector that drives the intrinsic apoptotic pathway (it causes MOMP and cytochrome c release and is sequestered by pro-survival members), so it participates directly in positively regulating intrinsic apoptotic signalling. Well supported and not in current GOA. Supporting Evidence: PMID:23055042 we demonstrated a novel human BH3-only protein (designated as Bop) which could induce apoptosis in a BH3 domain-dependent manner PMID:23055042 Bop was partially required for VCR induced cell death |
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Download this section (compressed HTML)Q: In which cell types and stimuli is RTL10/Bop a physiologically important BH3-only apoptosis effector, and is it transcriptionally or post-translationally regulated like canonical BH3-only proteins?
Experiment: Test BH3 point mutants (L118A, D123A) for loss of pro-apoptotic activity, Bcl-2-family binding and VDAC1 engagement, and measure MOMP (ΞΟm, cytochrome c) in cells with RTL10 gain- and loss-of-function.
Hypothesis: RTL10/Bop drives intrinsic apoptosis through BH3-dependent engagement of VDAC1 and Bcl-2 family proteins.
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