Affinage

BICD1

Protein bicaudal D homolog 1 · UniProt Q96G01

Length
975 aa
Mass
110.8 kDa
Annotated
2026-06-09
13 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BICD1 is a coiled-coil dynein motor adaptor that links specific cargoes to the dynein complex and thereby controls their intracellular trafficking and the downstream signaling and degradative outcomes that depend on it (PMID:25084392, PMID:30464225). Its C-terminal CC3 region engages cargo proteins including Rab6, RanBP2, and HIF-1α, while its N-terminus mediates dynein recruitment and also binds the ESCRT component PTPN23 (PMID:25084392, PMID:32079660, PMID:42156301). Through this adaptor activity BICD1 drives lysosomal degradation of BDNF-activated neurotrophin receptors p75NTR and TrkB, with loss of either BICD1 or PTPN23 causing receptor accumulation in swollen vacuole-like compartments (PMID:32079660). In a distinct trafficking role, BICD1 binds PAR1 and promotes its endocytosis (PMID:38607237). Under hypoxia, BICD1 binds HIF-1α and dynein intermediate chain to mediate HIF-1α nuclear translocation and hypoxia-induced glycolytic reprogramming, an interaction enhanced by AKT activation and GSK3β loss; BICD1 itself is transcriptionally controlled, being induced by YAP and by KDM4E-mediated reduction of H3K9me3 at its promoter (PMID:30464225, PMID:38607237, PMID:42156301). Biallelic loss-of-function frameshift variants in BICD1 that abolish the protein cause peripheral neuropathy and hearing loss (PMID:37240244). A conserved role in motor-dependent neuronal morphogenesis is supported by the C. elegans ortholog, which regulates dendrite branching in a pathway with dynein and kinesin-1 (PMID:21205795).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1997 Low

    Establishing BICD1's molecular identity, cloning revealed a coiled-coil protein homologous to Drosophila Bicaudal-D, framing the initial hypothesis that it participates in cytoskeleton-based intracellular sorting.

    Evidence cDNA cloning, sequence analysis, and Northern blot in brain, heart, and skeletal muscle

    PMID:9367685

    Open questions at the time
    • No direct functional assay; sorting role inferred from sequence homology only
    • No cargo or motor partner identified
  2. 2008 Medium

    A regulatory SNP linking reduced BICD1 expression to shorter telomeres implicated BICD1 in telomere length homeostasis, though by association rather than mechanism.

    Evidence Genome-wide linkage, fine-mapping, and leukocyte eQTL analysis

    PMID:18487243

    Open questions at the time
    • No direct functional link between BICD1 protein and telomere maintenance demonstrated
    • Mechanism connecting an adaptor protein to telomere length unexplained
  3. 2011 Medium

    Genetic epistasis in C. elegans placed the BICD1 ortholog in a conserved motor pathway, establishing a role in neuronal dendrite morphogenesis alongside dynein and kinesin-1.

    Evidence RNAi, genetic epistasis with dhc-1, unc-116, and unc-5, and cell-specific expression in PVD neurons

    PMID:21205795

    Open questions at the time
    • Direct physical interaction with motor components not biochemically shown
    • Relevance to mammalian BICD1 function inferred from orthology
  4. 2014 Medium

    Crystallization of the CC3 domain and preparation of a CC3-active Rab6 complex defined the structural cargo-binding module that links Rab6 and RanBP2 to dynein.

    Evidence X-ray crystallography to 1.50 Å and complex preparation with constitutively active Rab6

    PMID:25084392

    Open questions at the time
    • Functional validation of the CC3-Rab6 interaction not described in the report
    • No full structure of the adaptor-motor-cargo assembly
  5. 2018 High

    Identifying BICD1 as the adaptor that couples HIF-1α to dynein for nuclear translocation revealed a signaling function beyond canonical cargo transport, controlling hypoxic metabolic reprogramming.

    Evidence Reciprocal co-IP, siRNA, overexpression, AKT/GSK3β modulation, and functional readouts (glycolysis, ROS, apoptosis, in vivo wound healing) in mesenchymal stem cells

    PMID:30464225

    Open questions at the time
    • Structural basis of the HIF-1α-BICD1 interaction not resolved in this study
    • How AKT/GSK3β signaling biochemically enhances binding unclear
  6. 2020 High

    Discovery of the BICD1-PTPN23 interaction connected the adaptor to the ESCRT machinery, establishing BICD1 as a determinant of lysosomal degradation of activated neurotrophin receptors.

    Evidence Interactome proteomics, domain mapping, and BICD1/PTPN23 knockdown with receptor-trafficking microscopy (p75NTR, TrkB)

    PMID:32079660

    Open questions at the time
    • PTPN23 binds the N-terminus and is not a canonical cargo; the mechanistic interplay with dynein recruitment at the same region unresolved
    • Single lab; reciprocal validation of the receptor-degradation pathway limited
  7. 2023 Medium

    Biallelic loss-of-function variants abolishing BICD1 protein tied the gene to a human Mendelian phenotype of peripheral neuropathy and hearing loss.

    Evidence Exome sequencing, segregation, and western blot of patient fibroblasts confirming protein absence

    PMID:37240244

    Open questions at the time
    • Single family; replication needed for definitive causality
    • Mechanism linking BICD1 loss to specific neuropathy and auditory phenotypes not established
  8. 2024 Medium

    Identification of BICD1 as a PAR1 interactor that drives PAR1 endocytosis, and as a target of KDM4E-mediated H3K9me3 demethylation, extended its adaptor role to receptor signaling control in cancer cells.

    Evidence KDM4E manipulation, ChIP for H3K9me3 at the BICD1 promoter, co-IP of BICD1-PAR1, and functional assays in triple-negative breast cancer cells

    PMID:38607237

    Open questions at the time
    • Whether dynein is required for BICD1-mediated PAR1 endocytosis not tested
    • Single lab; direct vs. indirect nature of BICD1-PAR1 binding not fully delineated
  9. 2026 Medium

    Mapping HIF-1α binding to the CC3 domain and identifying YAP as a transcriptional activator of BICD1 integrated the adaptor's signaling role with upstream control of its own expression.

    Evidence ChIP for YAP at the BICD1 promoter, domain-mapped co-IP of CC3 with HIF-1α, knockdown/overexpression, and xenograft model

    PMID:42156301

    Open questions at the time
    • Structural detail of the CC3-HIF-1α interface not resolved
    • Single lab; in vivo relevance beyond the xenograft system unexplored

Open questions

Synthesis pass · forward-looking unresolved questions
  • How BICD1 selects among its diverse cargoes (Rab6, RanBP2, HIF-1α, PAR1) and coordinates dynein recruitment with ESCRT-dependent degradation versus nuclear delivery remains unresolved.
  • No unified structural model of cargo-specific BICD1-dynein assemblies
  • Mechanism reconciling N-terminal PTPN23 binding with N-terminal dynein recruitment unknown
  • Tissue-specific basis of the human neuropathy/hearing-loss phenotype uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0008092 cytoskeletal protein binding 2
Localization
GO:0005768 endosome 1 GO:0005829 cytosol 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-8953897 Cellular responses to stimuli 1 R-HSA-9609507 Protein localization 1
Partners
DYNC1I (DYNEIN INTERMEDIATE CHAIN)HIF1APAR1 (F2R)PTPN23RAB6RANBP2

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 BICD1 encodes a coiled-coil protein with amphipathic helices and a leucine zipper motif, structurally homologous to Drosophila Bicaudal-D, and is expressed in brain, heart, and skeletal muscle, suggesting it is a component of a cytoskeleton-based mRNA sorting mechanism. cDNA cloning, predicted amino acid sequence analysis, Northern blot analysis Genomics Low 9367685
2008 A regulatory SNP (rs2630578) in intron 1 of BICD1 is associated with reduced BICD1 mRNA levels (44% lower in C allele carriers) and shorter telomere length in leukocytes, implicating BICD1 in telomere length homeostasis. Genome-wide linkage analysis, fine-mapping, quantitative mRNA expression analysis in leukocytes Human molecular genetics Medium 18487243
2011 C. elegans bicd-1 (BICD1 ortholog) regulates dendrite branch formation in PVD sensory neurons and operates in a conserved pathway with dynein component dhc-1 and kinesin-1 component unc-116, and interacts genetically with the repulsive guidance receptor unc-5. RNAi knockdown, genetic epistasis analysis, cell-specific expression studies Development (Cambridge, England) Medium 21205795
2014 The C-terminal coiled-coil region (CC3) of mouse BICD1 was crystallized and diffraction data collected to 1.50 Å resolution; CC3 links cargo proteins such as Rab6 and RanBP2 to the dynein motor complex, and a complex of CC3 with constitutively active Rab6 was prepared for structural analysis. X-ray crystallography, complex preparation with constitutively active Rab6 mutant Acta crystallographica. Section F, Structural biology communications Medium 25084392
2018 BICD1 acts as a dynein motor adaptor that mediates HIF1α nuclear translocation in mesenchymal stem cells under hypoxia; hypoxia stimulates direct binding of HIF1α to BICD1 and to dynein intermediate chain (Dynein IC), and this interaction is abolished by BICD1 silencing. Akt activation and GSK3β silencing enhance HIF1α-BICD1 binding and nuclear translocation. BICD1 silencing abolished hypoxia-induced glycolytic reprogramming and increased mitochondrial ROS and apoptosis. Co-immunoprecipitation (direct binding), siRNA knockdown, overexpression, Akt inhibition/activation, GSK3β silencing, functional readouts (glycolysis, ROS, apoptosis, in vivo wound healing) Cell death and differentiation High 30464225
2020 PTPN23, a member of the ESCRT machinery, was identified as a BICD1 interactor; molecular mapping showed PTPN23 binds the N-terminus of BICD1 (the same region essential for dynein recruitment), but is not a canonical BICD1 cargo. Loss of PTPN23 phenocopies BICD1 knockdown, causing accumulation of BDNF-activated p75NTR and TrkB in swollen vacuole-like compartments, establishing BICD1 as a key factor for lysosomal degradation of activated neurotrophin receptors. Proteomics/mass spectrometry (BICD1 interactome), molecular domain mapping, BICD1 and PTPN23 knockdown with endosomal trafficking readouts (fluorescence microscopy of receptor accumulation) Journal of cell science High 32079660
2023 Biallelic loss-of-function frameshift variants in BICD1 (c.1683dup) cause complete absence of BICD1 protein (detected by western blot of patient fibroblasts) and are associated with peripheral neuropathy and hearing loss in a human family. Exome sequencing, segregation analysis, western blotting of patient-derived fibroblasts, RNA analysis International journal of molecular sciences Medium 37240244
2024 KDM4E activates BICD1 expression by reducing H3K9me3 deposition at the BICD1 promoter; BICD1 physically interacts with PAR1 and promotes PAR1 endocytosis, blocking PAR1 signaling in triple-negative breast cancer cells. KDM4E knockdown/overexpression, ChIP (H3K9me3 at BICD1 promoter), Co-immunoprecipitation (BICD1-PAR1 interaction), functional assays (cell viability, migration, apoptosis) Molecular carcinogenesis Medium 38607237
2026 YAP directly binds the BICD1 promoter and enhances its transcriptional activity. BICD1 interacts with HIF-1α via its C-terminal CC3 domain, promoting HIF-1α nuclear translocation and transcriptional activity. AKT activation or GSK3β knockdown enhances the BICD1-HIF-1α interaction. ChIP (YAP binding to BICD1 promoter), Co-immunoprecipitation (BICD1 CC3 domain with HIF-1α), BICD1 knockdown/overexpression, domain deletion mapping, in vivo xenograft model Pathology, research and practice Medium 42156301

Source papers

Stage 0 corpus · 13 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Genome-wide association study identifies BICD1 as a susceptibility gene for emphysema. American journal of respiratory and critical care medicine 96 20709820
2008 A regulatory SNP of the BICD1 gene contributes to telomere length variation in humans. Human molecular genetics 52 18487243
2011 C. elegans bicd-1, homolog of the Drosophila dynein accessory factor Bicaudal D, regulates the branching of PVD sensory neuron dendrites. Development (Cambridge, England) 51 21205795
1997 A human homologue (BICD1) of the Drosophila bicaudal-D gene. Genomics 31 9367685
2018 BICD1 mediates HIF1α nuclear translocation in mesenchymal stem cells during hypoxia adaptation. Cell death and differentiation 30 30464225
2020 PTPN23 binds the dynein adaptor BICD1 and is required for endocytic sorting of neurotrophin receptors. Journal of cell science 12 32079660
2015 hTERT, BICD1 and chromosome 18 polymorphisms associated with telomere length affect kidney allograft function after transplantation. Kidney & blood pressure research 9 25792135
2024 Baicalein promotes KDM4E to induce BICD1 and inhibit triple-negative breast cancer progression by blocking PAR1 signaling. Molecular carcinogenesis 7 38607237
2019 A genome-wide by PM10 interaction study identifies novel loci for lung function near BICD1 and IL1RN-IL1F10 genes in Korean adults. Chemosphere 5 31846791
2014 Crystallographic characterization of the C-terminal coiled-coil region of mouse Bicaudal-D1 (BICD1). Acta crystallographica. Section F, Structural biology communications 4 25084392
2016 BICD1 and Chromosome 18 Polymorphisms Associated With Recipients' Telomere Length Affect Kidney Allograft Function After Transplantation. Transplantation proceedings 3 27496426
2026 YAP-induced BICD1 promotes hepatocellular carcinoma cell proliferation, stemness, and migration by facilitating the nuclear translocation of HIF-1α. Pathology, research and practice 0 42156301
2023 Biallelic Loss-of-Function Variants in BICD1 Are Associated with Peripheral Neuropathy and Hearing Loss. International journal of molecular sciences 0 37240244

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