Affinage

BIRC7

Baculoviral IAP repeat-containing protein 7 · UniProt Q96CA5

Length
298 aa
Mass
32.8 kDa
Annotated
2026-06-09
29 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BIRC7 (ML-IAP/Livin) is a single-BIR/RING-domain inhibitor of apoptosis that restrains effector caspase activity and couples apoptotic control to ubiquitin signaling (PMID:11084335, PMID:22902369). Its anti-apoptotic function depends on the integrity of its BIR domain, which is only a weak direct inhibitor of caspases 3 and 9; the dominant mechanism is high-affinity sequestration of Smac/DIABLO, which displaces Smac from XIAP and thereby preserves XIAP-mediated caspase inhibition (PMID:11801603, PMID:15485396). Crystal structures of the BIR domain bound to Smac-derived and phage-derived peptides defined the peptide-binding groove and enabled selective high-affinity peptide antagonists (PMID:12846571). The RING domain confers E3 ubiquitin ligase activity: it dimerizes to lock the donor ubiquitin on the E2 UbcH5B~Ub conjugate in a transfer-competent orientation, and this same RING activity drives BIRC7 autodegradation in response to bivalent IAP antagonists (PMID:22902369, PMID:22853455). BIRC7 is also processed during apoptosis by cleavage at Asp52 to a truncated form (tLivin) that paradoxically acquires pro-apoptotic activity, a conversion exploited by NK cells to limit tumor growth in vivo (PMID:16806840, PMID:19549891). Beyond core apoptotic control, BIRC7 binds C-RAF and restrains its protein level, MAPK activation, and melanoma cell migration, and it suppresses autophagy through ATG5 and BECN1 to promote EMT and metastasis (PMID:22711539, PMID:32064154).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2000 Medium

    Established BIRC7 as a domain-defined IAP and showed the BIR domain is necessary for anti-apoptotic function, framing the question of how a single-BIR protein blocks cell death.

    Evidence Deletion/mutational analysis with overexpression apoptosis assays in cell lines

    PMID:11084335

    Open questions at the time
    • Direct caspase inhibition proposed but not reconstituted in vitro
    • RING-domain function not addressed
    • No structural basis for BIR activity
  2. 2002 High

    Identified Smac/DIABLO as a high-affinity BIR-domain ligand, shifting the mechanistic model away from direct caspase inhibition toward Smac sequestration.

    Evidence Co-IP, Smac-peptide binding assays, single-residue mutagenesis, cell-death rescue

    PMID:11801603

    Open questions at the time
    • Did not quantify the effect on endogenous XIAP-Smac equilibrium
    • Structural interface not yet resolved
  3. 2003 High

    Resolved the atomic structure of the BIR–peptide interface, enabling design of antagonists selective for BIRC7 over XIAP.

    Evidence X-ray crystallography, phage display, synthetic peptide SAR, affinity measurements

    PMID:12846571

    Open questions at the time
    • Structures use peptide surrogates rather than full-length Smac
    • No structure of the RING/E3 module
  4. 2005 High

    Directly tested the competing mechanisms, showing BIR is only a weak caspase inhibitor and that Smac sequestration disrupting the XIAP-Smac complex is the primary anti-apoptotic route.

    Evidence In vitro caspase assays, BIR engineering, co-IP of endogenous ML-IAP-Smac and XIAP-Smac complexes

    PMID:15485396

    Open questions at the time
    • Quantitative contribution of residual direct caspase inhibition unresolved
    • Does not address RING-dependent functions
  5. 2006 Medium

    Mapped a defined apoptotic cleavage site at Asp52 and showed cleavage can occur by a non-canonical, partly caspase-independent protease, opening the question of how an IAP is itself processed during death.

    Evidence Asp52 mutagenesis, deletion mapping, Omi/HtrA2 RNAi, zVAD-fmk treatment across stimuli

    PMID:16806840

    Open questions at the time
    • Identity of the responsible protease not established
    • Functional consequence of cleavage not defined here
  6. 2009 Medium

    Showed cleavage generates a truncated tLivin with paradoxical pro-apoptotic activity that NK cells exploit to suppress tumors, redefining BIRC7 as a context-dependent regulator of death.

    Evidence Caspase-site point mutants, NK-cell-depleted xenograft mouse models, in vivo growth assays

    PMID:19549891

    Open questions at the time
    • Molecular basis of tLivin pro-apoptotic gain-of-function unclear
    • Single lab, limited tumor models
  7. 2012 High

    Defined the catalytic mechanism of the RING E3 activity, showing dimerization positions the UbcH5B~Ub conjugate for ubiquitin transfer.

    Evidence Crystal structure of dimeric RING–UbcH5B~Ub, NMR, mutagenesis, in vitro ubiquitination

    PMID:22902369

    Open questions at the time
    • Physiological substrates of the ligase not identified in this study
    • Regulation of dimerization in cells unknown
  8. 2012 Medium

    Linked RING activity to drug-induced self-destruction, showing bivalent IAP antagonists trigger BIRC7 autodegradation independent of c-IAP1/2.

    Evidence IAP antagonist treatment, proteasome rescue, RING mutants, c-IAP1/2 knockout/knockdown lines

    PMID:22853455

    Open questions at the time
    • Whether degradation is autoubiquitination vs trans-ubiquitination not fully resolved
    • E2 used in cells not pinpointed
  9. 2012 Medium

    Extended BIRC7 function beyond apoptosis by showing it binds C-RAF and limits its stability, MAPK signaling, and melanoma migration.

    Evidence Co-IP, siRNA knockdown with C-RAF Western blot, MAPK and migration assays

    PMID:22711539

    Open questions at the time
    • Whether C-RAF is a direct ubiquitination substrate not shown
    • Single lab, reciprocal validation limited
  10. 2018 Low

    Placed BIRC7 downstream of miR-23a in controlling hepatocarcinoma apoptosis, adding an upstream regulatory layer.

    Evidence miRNA/siRNA transfection, overexpression rescue, caspase-3 assay, flow cytometry

    PMID:30280770

    Open questions at the time
    • No direct miR-23a–BIRC7 binding confirmation
    • Single cell line, no orthogonal method
  11. 2020 Medium

    Connected BIRC7 to autophagy suppression via ATG5/BECN1 and to EMT/metastasis, with mTOR co-targeting as a synergistic vulnerability.

    Evidence Gain/loss-of-function, electron microscopy, ATG5/BECN1/EMT Westerns, invasion assays, xenografts

    PMID:32064154

    Open questions at the time
    • Mechanism by which BIRC7 modulates ATG5/BECN1 expression undefined
    • Single tumor type
  12. 2022 Low

    Identified BIRC7 as a HIF-1α transcriptional target, linking its expression to the hypoxic tumor microenvironment.

    Evidence Luciferase promoter reporter, hypoxia RNA-seq, qRT-PCR, siRNA knockdown phenotypes

    PMID:35747741

    Open questions at the time
    • No ChIP confirming HIF-1α binding to endogenous promoter
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • The endogenous substrate repertoire of the BIRC7 RING ligase and the protease that generates tLivin remain unidentified, leaving the link between its E3 activity and its non-apoptotic roles (C-RAF, autophagy) mechanistically open.
  • No validated physiological ubiquitination substrate
  • tLivin-generating protease unidentified
  • Whether C-RAF and autophagy effects are RING-dependent not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 2 GO:0098772 molecular function regulator activity 2 GO:0140096 catalytic activity, acting on a protein 1 GO:0140313 molecular sequestering activity 1
Pathway
R-HSA-5357801 Programmed Cell Death 3 R-HSA-392499 Metabolism of proteins 2
Partners
DIABLORAF1UBE2D2

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 ML-IAP (BIRC7) contains a single BIR domain and RING finger motif; deletion and mutational analysis demonstrated that integrity of the BIR domain is required for anti-apoptotic function, likely through direct inhibition of downstream effector caspases. Deletion and mutational analysis; overexpression in cell lines with apoptosis assays Current biology : CB Medium 11084335
2002 ML-IAP BIR domain physically interacts with SMAC/DIABLO through its BIR domain with low nanomolar affinity; single amino acid mutations in either SMAC N-terminus or ML-IAP BIR abolished this interaction; SMAC coexpression or SMAC peptides abrogated ML-IAP-mediated inhibition of cell death. Co-immunoprecipitation, binding assays with SMAC peptides, single amino acid mutagenesis, cell-based apoptosis assays The Journal of biological chemistry High 11801603
2003 X-ray crystal structures of ML-IAP BIR domain in complex with Smac-derived and phage-derived peptides revealed the peptide-binding surface; structure-activity relationships showed that modifications at Pro3' of the Smac peptide confer 7-fold greater affinity for ML-IAP-BIR with ~100-fold selectivity over XIAP-BIR3. X-ray crystallography, phage display, synthetic peptide SAR, binding affinity measurements Biochemistry High 12846571
2005 ML-IAP BIR domain is a weak direct inhibitor of caspases 3 and 9; the primary anti-apoptotic mechanism of ML-IAP is sequestration of Smac/DIABLO, preventing it from antagonizing XIAP-mediated caspase inhibition. Increased ML-IAP expression results in formation of a ML-IAP–Smac complex and disruption of the endogenous XIAP–Smac interaction. In vitro caspase inhibition assays, BIR domain engineering, co-immunoprecipitation of endogenous ML-IAP–Smac and XIAP–Smac complexes, mutagenesis The Biochemical journal High 15485396
2006 Livin (ML-IAP) is proteolytically cleaved during apoptosis at residue Asp52 (within DHVD52); mutation of Asp52 to Ala or deletion of the adjacent region abrogated cleavage. Cleavage was largely independent of Omi/HtrA2 and for some stimuli independent of caspases, suggesting a non-canonical caspase mediates cleavage. Site-directed mutagenesis of Asp52, deletion mapping, RNAi knockdown of Omi/HtrA2, pan-caspase inhibitor (zVAD-fmk) treatment, multiple apoptotic stimuli Journal of dermatological science Medium 16806840
2009 Livin (ML-IAP) is unique among IAP members in being specifically cleaved by caspases upon strong apoptotic stimulus to produce a truncated protein (tLivin) with paradoxical pro-apoptotic activity; NK cells induce Livin cleavage to tLivin which inhibits tumor growth in vivo. Point mutations to eliminate caspase cleavage site, tumor xenograft animal model with NK cell-depleted mice, in vivo tumor growth assays Cancer research Medium 19549891
2012 The crystal structure of the dimeric BIRC7 RING domain in complex with E2 UbcH5B covalently linked to ubiquitin (UbcH5B~Ub) revealed that RING dimerization stabilizes the donor Ub through extensive noncovalent interactions with UbcH5B and both RING subunits; mutations disrupting these interactions or RING dimerization reduced UbcH5B~Ub binding affinity and ubiquitination activity. X-ray crystallography, NMR peak-shift analysis, mutagenesis, in vitro ubiquitination assays, binding affinity measurements Nature structural & molecular biology High 22902369
2012 ML-IAP directly binds C-RAF kinase; ML-IAP depletion leads to increased C-RAF protein levels, MAPK activation, and increased cell migration in melanoma cells, indicating ML-IAP controls C-RAF protein stability and cell migration. Co-immunoprecipitation (ML-IAP–C-RAF interaction), siRNA knockdown with Western blot for C-RAF levels, MAPK activation assays, migration assays The Journal of biological chemistry Medium 22711539
2012 ML-IAP undergoes proteasomal degradation in response to bivalent (but not monovalent) IAP antagonists; this degradation requires ML-IAP's own ubiquitin ligase (RING domain) activity and is independent of c-IAP1 or c-IAP2. IAP antagonist treatment, proteasome inhibitor rescue, RING domain mutants, c-IAP1/c-IAP2 knockout/knockdown cell lines The Biochemical journal Medium 22853455
2018 MicroRNA-23a down-regulates KIAP (BIRC7) expression; inhibition of KIAP enhanced the pro-apoptotic effect of miR-23a, while overexpression of KIAP abrogated it, placing KIAP downstream of miR-23a in a pathway controlling hepatocarcinoma cell apoptosis and caspase-3 activation. miRNA transfection, siRNA knockdown, plasmid overexpression, Western blot, caspase-3 activity assay, flow cytometry European review for medical and pharmacological sciences Low 30280770
2020 BIRC7 suppresses autophagy through modulating expression of ATG5 and BECN1; this autophagy suppression drives epithelial-mesenchymal transition (EMT) and metastasis in papillary thyroid carcinoma cells; combined targeting of BIRC7 and mTOR enhances autophagy and achieves synergistic anti-metastatic effects in vitro and in vivo. BIRC7 overexpression and siRNA knockdown, transmission electron microscopy, Western blot for ATG5/BECN1/EMT markers, wound-healing and invasion assays, xenograft tumor model American journal of cancer research Medium 32064154
2022 BIRC7 is a transcriptional downstream target of HIF-1α in melanoma; its promoter contains HIF-1α binding sites confirmed by luciferase assay; BIRC7 knockdown reversed the pro-tumorigenic effects of HIF-1α under hypoxia. Luciferase reporter assay (HIF-1α binding to BIRC7 promoter), RNA-seq under hypoxia, qRT-PCR, Western blot, siRNA knockdown with cellular function assays Clinical, cosmetic and investigational dermatology Low 35747741

Source papers

Stage 0 corpus · 29 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 ML-IAP, a novel inhibitor of apoptosis that is preferentially expressed in human melanomas. Current biology : CB 336 11084335
2012 BIRC7-E2 ubiquitin conjugate structure reveals the mechanism of ubiquitin transfer by a RING dimer. Nature structural & molecular biology 281 22902369
2002 SMAC negatively regulates the anti-apoptotic activity of melanoma inhibitor of apoptosis (ML-IAP). The Journal of biological chemistry 119 11801603
2005 Engineering ML-IAP to produce an extraordinarily potent caspase 9 inhibitor: implications for Smac-dependent anti-apoptotic activity of ML-IAP. The Biochemical journal 112 15485396
2000 KIAP, a novel member of the inhibitor of apoptosis protein family. Biochemical and biophysical research communications 104 11162435
2003 Melanoma inhibitor of apoptosis protein (ML-IAP) is a target for immune-mediated tumor destruction. Proceedings of the National Academy of Sciences of the United States of America 86 12626761
2003 Induction of apoptosis in tumor cells by siRNA-mediated silencing of the livin/ML-IAP/KIAP gene. Oncogene 81 14614456
2003 Structure and function analysis of peptide antagonists of melanoma inhibitor of apoptosis (ML-IAP). Biochemistry 79 12846571
2007 Livin/ML-IAP as a new target for cancer treatment. Cancer letters 67 17218055
2005 Aberrant expression and potency as a cancer immunotherapy target of inhibitor of apoptosis protein family, Livin/ML-IAP in lung cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 58 15709165
2009 The inhibitor of apoptosis protein Livin (ML-IAP) plays a dual role in tumorigenicity. Cancer research 39 19549891
2017 Livin/BIRC7 expression as malignancy marker in adrenocortical tumors. Oncotarget 31 28030838
2013 Expedient synthesis of highly potent antagonists of inhibitor of apoptosis proteins (IAPs) with unique selectivity for ML-IAP. ACS chemical biology 26 23323685
2010 Expression and functional role of inhibitor-of-apoptosis protein livin (BIRC7) in neuroblastoma. Biochemical and biophysical research communications 25 20691667
2012 Role of melanoma inhibitor of apoptosis (ML-IAP) protein, a member of the baculoviral IAP repeat (BIR) domain family, in the regulation of C-RAF kinase and cell migration. The Journal of biological chemistry 24 22711539
2020 BIRC7 promotes epithelial-mesenchymal transition and metastasis in papillary thyroid carcinoma through restraining autophagy. American journal of cancer research 23 32064154
2011 Immunity to the melanoma inhibitor of apoptosis protein (ML-IAP; livin) in patients with malignant melanoma. Cancer immunology, immunotherapy : CII 21 22033581
2015 Birc7: A Late Fiber Gene of the Crystalline Lens. Investigative ophthalmology & visual science 17 26218911
2012 Characterization of ML-IAP protein stability and physiological role in vivo. The Biochemical journal 16 22853455
2006 Proteolytic cleavage of Livin (ML-IAP) in apoptotic melanoma cells potentially mediated by a non-canonical caspase. Journal of dermatological science 11 16806840
2016 BIRC7 and KLF4 expression in benign and malignant lesions of pancreas and their clinicopathological significance. Cancer biomarkers : section A of Disease markers 10 27802195
2020 BIRC7 and STC2 Expression Are Associated With Tumorigenesis and Poor Outcome in Extrahepatic Cholangiocarcinoma. Technology in cancer research & treatment 8 33234031
2009 Melanoma inhibitor of apoptosis protein (ML-IAP) specific cytotoxic T lymphocytes cross-react with an epitope from the auto-antigen SS56. The Journal of investigative dermatology 8 19212346
2013 Comparative study of clinicopathological significance, BIRC7, and STC2 expression between squamous cell/adenosquamous carcinomas and adenocarcinoma of gallbladder. Neoplasma 6 23906305
2012 BIRC7 gene in channel catfish (Ictalurus punctatus): identification and expression analysis in response to Edwardsiella tarda, Streptococcus iniae and Channel catfish Hemorrhage Reovirus. Fish & shellfish immunology 6 22510211
2006 Expression of BIRC7 protein and mRNA in non-Hodgkin's lymphoma. Leukemia & lymphoma 5 16840203
2022 BIRC7 is Beneficial for Melanoma Progression and Hypoxic Response. Clinical, cosmetic and investigational dermatology 2 35747741
2026 Engineering of the Melanoma Inhibitor of Apoptosis (ML-IAP) Anticancer Peptide Through Comprehensive In Silico Approaches. Human mutation 0 41969613
2018 MicroRNA-23a induces apoptosis of hepatocarcinoma cell line MHCC97H via down-regulating KIAP: a mechanism study. European review for medical and pharmacological sciences 0 30280770

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