id: A0JNT9 gene_symbol: Bicdl1 product_type: PROTEIN status: DRAFT taxon: id: NCBITaxon:10090 label: Mus musculus description: >- Bicdl1 (BICD family-like cargo adapter 1; also known as BICDR-1) is a coiled-coil activating adaptor for cytoplasmic dynein-1. Its N-terminal coiled-coil region binds the dynein tail and dynactin and assembles a dynein-dynactin-adaptor complex that is highly processive; with mouse BICDR-1 the complex preferentially contains two dynein dimers (and, on microtubules, two adaptor molecules), which increases motor speed and force. Its C-terminal BICDL1/2-like domain binds the GTP-bound form of the small GTPase Rab6 (Rab6A and, most strongly, Rab6B) directly, with Lys-512 required for binding, so that BICDR-1 couples dynein-dynactin to Rab6-positive post-Golgi secretory vesicles. It also binds the tail of the kinesin-3 KIF1C. In cultured cells and young neurons BICDR-1 concentrates around the centrosome together with dynein-dynactin and Rab6/NPY vesicles, in a microtubule- and dynein-dependent manner, and it shifts Rab6 vesicle traffic toward the microtubule minus end. Expression is high in early embryonic and undifferentiated neural tissue, kidney and developing eye and declines as neurons extend neurites; sustained expression in cultured neurons retains secretory vesicles in the cell body and suppresses neurite outgrowth. alternative_products: - name: '1' id: A0JNT9-1 - name: '2' id: A0JNT9-2 sequence_note: VSP_027971, VSP_027973 - name: '3' id: A0JNT9-3 sequence_note: VSP_027970, VSP_027972, VSP_027974, VSP_027975 existing_annotations: - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:20360680 qualifier: enables supporting_entities: - UniProtKB:O43896 review: summary: Interaction of mouse BICDR-1 with the C-terminal tail of the kinesin-3 KIF1C (human O43896), found in a yeast two-hybrid screen and confirmed by binding assays with BICDR-1 fragments. action: MODIFY reason: The interaction is well supported, but bare protein binding is uninformative. The partner is a kinesin motor, so the informative term is kinesin binding. KIF1C binding is peripheral to the core dynein-adaptor role (the paper concludes dynein dominates BICDR-1/Rab6 vesicle transport), so the replacement is non-core. proposed_replacement_terms: - id: GO:0019894 label: kinesin binding supported_by: - reference_id: PMID:20360680 supporting_text: Both full-length BICDR-1 and an N-terminal region of BICDR-1, amino acids 1–353, interact with the C-terminal tail domain of Kif1C, amino acids 811–1090 and not with other tail regions of Kif1C or other kinesin motors, such as Kif5 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:20360680 qualifier: enables supporting_entities: - UniProtKB:P35279 review: summary: Direct binding of the BICDR-1 C-terminal domain to Rab6A (P35279), shown with purified proteins and GTP-dependent in yeast two-hybrid. action: MODIFY reason: Bare protein binding is uninformative; Rab6A is a small GTPase and the binding is direct, GTP-state dependent and abolished by K512M. Replace with small GTPase binding, which the gene already carries by IDA from the same paper. proposed_replacement_terms: - id: GO:0031267 label: small GTPase binding supported_by: - reference_id: PMID:20360680 supporting_text: Binding of BICDR-1 to Rab6A is direct because the purified His-tagged C-terminus of BICDR-1 (amino acids 382–577) interacts with purified GST-Rab6A and GST-Rab6B and not with GST only - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:20360680 qualifier: enables supporting_entities: - UniProtKB:P61294 review: summary: Direct binding of the BICDR-1 C-terminal domain to Rab6B (P61294), the neuronal Rab6 isoform, which BICDR-1 binds most strongly. action: MODIFY reason: As for Rab6A, the informative term for direct Rab6B binding is small GTPase binding, already carried by this gene by IDA from the same paper. proposed_replacement_terms: - id: GO:0031267 label: small GTPase binding supported_by: - reference_id: PMID:20360680 supporting_text: Interestingly, BICDR-1 binds most strongly to the neuron-specific isoform Rab6B - term: id: GO:0005813 label: centrosome evidence_type: IDA original_reference_id: PMID:20360680 qualifier: located_in review: summary: Endogenous BICDR-1 stains intensely around the gamma-tubulin-labelled centrosome, and this localization depends on microtubules, gamma-tubulin, Rab6A and dynein/dynactin. action: ACCEPT reason: Direct immunofluorescence evidence. Strictly the protein is pericentrosomal (on Rab6 vesicles clustered around the centrosome, together with dynein-dynactin) rather than a structural centriole component, but centrosome is the GO term used for this localization and it reflects the site where BICDR-1 concentrates its cargo. The endogenous staining was done in cultured cell lines with an anti-BICDR-1 antibody; overexpressed mouse BICDR-1 behaves the same way. supported_by: - reference_id: PMID:20360680 supporting_text: Fluorescence microscopic analysis showed an intense perinuclear BICDR-1 staining (Supplementary Figure S2C–E) specifically localized around the γ-tubulin-labelled centrosome - reference_id: PMID:20360680 supporting_text: These data suggest that the pericentrosomal BICDR-1 localization is microtubule and γ-tubulin dependent. - term: id: GO:0005813 label: centrosome evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in supporting_entities: - UniProtKB-SubCell:SL-0048 review: summary: UniProt subcellular-location mapping of the curated centrosome localization, which rests on PMID:20360680. action: ACCEPT reason: Same claim as the IDA row, which it reinforces. supported_by: - reference_id: PMID:20360680 supporting_text: Fluorescence microscopic analysis showed an intense perinuclear BICDR-1 staining (Supplementary Figure S2C–E) specifically localized around the γ-tubulin-labelled centrosome - term: id: GO:0005856 label: cytoskeleton evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in supporting_entities: - UniProtKB-SubCell:SL-0090 review: summary: UniProt subcellular-location mapping of "Cytoplasm, cytoskeleton", which UniProt bases on the cryo-EM structure of dynein-dynactin-BICDR1 on microtubules. action: MODIFY reason: True but general. The specific supported location carried by this gene is centrosome (pericentrosomal, IDA). BICDR-1 is also found on microtubules as part of the dynein-dynactin-adaptor transport complex, which is better expressed through the complex and process terms than through a generic cytoskeleton location. proposed_replacement_terms: - id: GO:0005813 label: centrosome supported_by: - reference_id: PMID:36071160 supporting_text: Here we develop a cryo-electron microscopy processing pipeline to solve the high-resolution structure of dynein-dynactin and the adaptor BICDR1 bound to microtubules. - term: id: GO:0031175 label: neuron projection development evidence_type: IMP original_reference_id: PMID:20360680 qualifier: involved_in review: summary: Sustained (over)expression of BICDR-1 in cultured hippocampal neurons reduces neurite outgrowth; the authors conclude that BICDR-1 restricts anterograde secretory transport and inhibits neuritogenesis early in differentiation, its normal down-regulation permitting outgrowth. action: MODIFY reason: The evidence is a gain-of-function (sustained expression) phenotype, and the direction of the effect is inhibitory, so the positive process term misstates it. The supported claim is negative regulation of neuron projection development, and even this is an indirect cellular consequence of where BICDR-1 positions Rab6 secretory vesicles rather than an activity executed within neurite growth. It is retained as a non-core regulatory role. Morpholino phenotypes in zebrafish in the same paper are not mouse evidence and are not used here. proposed_replacement_terms: - id: GO:0010977 label: negative regulation of neuron projection development supported_by: - reference_id: PMID:20360680 supporting_text: At 2, 3 and 4 days after transfection, BICDR-1-transfected neurons showed a marked reduction in neurite outgrowth compared with control cells transfected with an empty vector and β-galactosidase - reference_id: PMID:20360680 supporting_text: At early developmental stages, pericentrosomal BICDR-1 restricts secretory transport and inhibits neuritogenesis, whereas later during neuronal development the reduction in BICDR-1 expression permits anterograde transport required for neurite outgrowth. - term: id: GO:0031267 label: small GTPase binding evidence_type: IDA original_reference_id: PMID:20360680 qualifier: enables review: summary: The BICDR-1 C-terminus binds GTP-locked Rab6A but not GDP-locked Rab6A, binds purified Rab6A/B directly, and binding requires Lys-512; of 60 Rabs screened, Rab6A/B bind strongly. action: ACCEPT reason: Direct, specific, GTP-state-dependent binding to Rab6 is how BICDR-1 recognises its vesicle cargo and is a core part of its adaptor function. Rab GTPase binding (GO:0017137) is obsolete, so small GTPase binding is the appropriate term. supported_by: - reference_id: PMID:20360680 supporting_text: BICDR-1 strongly interacts with only one Rab subfamily, Rab6A/B (Figure 3A, square) and marginally with Rab11B and Rab12, but not with any of the other Rabs tested - reference_id: PMID:20360680 supporting_text: Moreover, both full-length BICDR-1 and a C-terminal region of BICDR-1, amino acids 382–577, interact with constitutively active GTPase-deficient Rab6A-Q72R and not with GDP-locked inactive Rab6A-T27N in the yeast two-hybrid assay - reference_id: PMID:20360680 supporting_text: showed that lysine 512 is required for binding to Rab6 - term: id: GO:0034452 label: dynactin binding evidence_type: IDA original_reference_id: PMID:20360680 qualifier: enables review: summary: GFP-BICDR-1 co-immunoprecipitates the major dynein and dynactin subunits and recruits dynactin to the pericentrosomal region; cryo-EM structures with purified mouse BICDR1 show its coiled coil running along the dynactin Arp1 filament and contacting the pointed end. action: ACCEPT reason: Dynactin binding is intrinsic to the activating-adaptor mechanism (adaptor, dynein and dynactin form the tripartite motor). The co-IP alone does not establish directness, but the structural studies with purified mouse protein confirm a direct dynactin interface. supported_by: - reference_id: PMID:20360680 supporting_text: Co-immunoprecipitation experiments from Hela cells transfected with GFP-BICDR-1 showed that BICDR-1 precipitates the major dynein/dynactin subunits, whereas no binding is seen with control GFP - reference_id: PMID:33734450 supporting_text: Extending our registry suggests that the positively charged site 1 loop on the pointed end binds to a negatively charged patch on BICDR1 - term: id: GO:0047496 label: vesicle transport along microtubule evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in supporting_entities: - PANTHER:PTN001281025 - ZFIN:ZDB-GENE-091204-439 review: summary: PAINT propagation from the deuterostome BICDL1 node PTN001281025 (PTHR32123:SF12), seeded by a zebrafish annotation. Mouse BICDR-1 itself links dynein-dynactin to Rab6 secretory vesicles, is required for their pericentrosomal clustering (siRNA), and shifts their transport toward microtubule minus ends. action: ACCEPT reason: Mouse Bicdl1 is inside the SF12 clade, and this species has its own experimental support for the process (loss-of-function in cultured cells and live imaging of Rab6/NPY vesicles), together with the biochemical mechanism (direct Rab6 binding plus dynein-dynactin activation). This is the core process the adaptor activity serves. supported_by: - reference_id: PMID:20360680 supporting_text: Vero cells transfected with three independent BICDR-1-siRNAs (Supplementary Figure S4A–C) clearly showed that, in the absence of BICDR-1, Rab6-positive vesicles no longer cluster around the centrosomal region, whereas Rab6 staining at the Golgi was unaffected - reference_id: PMID:20360680 supporting_text: These data suggest that increasing amounts of BICDR-1 in cells shift the transport of Rab6/NPY secretory vesicles to the microtubule minus-end (retrograde) direction. - term: id: GO:0055107 label: Golgi to secretory granule transport evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in supporting_entities: - MGI:MGI:1922915 - PANTHER:PTN001281025 review: summary: PAINT propagation from PTN001281025 seeded by this gene's own MGI IMP annotation from PMID:20360680. action: KEEP_AS_NON_CORE reason: The node placement is sound and mouse Bicdl1 is the experimental seed (its presence in the WITH/FROM is expected, not circular). The term describes the post-Golgi delivery of Rab6/NPY secretory carriers whose distribution BICDR-1 controls. BICDR-1 does not sort cargo from the Golgi into granules and does not affect exocytosis itself; its executed role is motor recruitment and activation on vesicles that have already left the Golgi, captured by vesicle transport along microtubule. Retained as a non-core, pathway-level description, consistent with the IMP row. supported_by: - reference_id: PMID:20360680 supporting_text: Together these data suggest that BICDR-1 does not influence secretory vesicle exocytosis but controls the distribution of secretory carriers. - term: id: GO:0055107 label: Golgi to secretory granule transport evidence_type: IMP original_reference_id: PMID:20360680 qualifier: involved_in review: summary: BICDR-1 knockdown abolishes pericentrosomal clustering of Rab6 secretory vesicles without affecting Rab6 at the Golgi; BICDR-1 expression redistributes NPY secretory carriers and the sites of their exocytosis. action: KEEP_AS_NON_CORE reason: The experimental data show BICDR-1 controls the positioning of post-Golgi Rab6/NPY secretory carriers, which is a legitimate part of Golgi-to-secretory-vesicle delivery, but the direct role is microtubule-based vesicle transport (dynein recruitment and activation), not Golgi export or granule formation. Same claim and action as the IBA row. supported_by: - reference_id: PMID:20360680 supporting_text: Vero cells transfected with three independent BICDR-1-siRNAs (Supplementary Figure S4A–C) clearly showed that, in the absence of BICDR-1, Rab6-positive vesicles no longer cluster around the centrosomal region, whereas Rab6 staining at the Golgi was unaffected - reference_id: PMID:20360680 supporting_text: Most NPY-GFP exocytotic events occur in the cell body of BICDR-1 neurons, whereas in control cells most events take place in developing neurites. - term: id: GO:0140660 label: cytoskeletal motor activator activity evidence_type: IDA original_reference_id: PMID:29420470 review: summary: Purified mouse BICDR1 assembles with dynein and dynactin into processive minus-end directed complexes that predominantly contain two dyneins and move faster and with more force than BICD2 complexes. action: NEW reason: The core molecular function of BICDR-1 is to activate dynein-dynactin motility (an activating adaptor). This is established directly with recombinant mouse BICDR1 in single-molecule motility and cryo-EM studies, and is a molecular function rather than a process, so the process-specific NEW bar on substrates does not apply. GO:0140660 is defined as binding to and increasing the activity of a motor protein, which matches the mechanism. Other activating adaptors (human BICD2, HOOK3) currently carry dynein complex binding rather than this term, so this is noted as a convention question in suggested_questions. supported_by: - reference_id: PMID:29420470 supporting_text: We conclude the majority of motile complexes containing BICD2 have one dynein, whereas both BICDR1 and HOOK3 preferentially recruit two. - reference_id: PMID:29420470 supporting_text: Previous work on BICDR1 in cells14 and HOOK3 in vitro5,10,11,19 showed complexes containing these adaptors move faster than those with BICD2. - reference_id: PMID:29420470 supporting_text: 'The following adaptors were codon optimized for Sf9 expression (Epoch Life Science): mouse BICDR1 (BICDL1)' - term: id: GO:0070840 label: dynein complex binding evidence_type: IDA original_reference_id: PMID:36071160 review: summary: Cryo-EM of dynein-dynactin with full-length purified mouse BICDR1 on microtubules shows two BICDR1 adaptors bound to the complex, both making similar contacts with the dynein heavy chains; GFP-BICDR-1 also co-precipitates dynein subunits. action: NEW reason: Direct binding to the dynein complex is an experimentally established mouse activity and is the term used for other dynein activating adaptors such as BICD2. It complements dynactin binding; together they describe the adaptor's motor-binding interface. supported_by: - reference_id: PMID:36071160 supporting_text: Full-length mouse BICDR with an N-terminal ZZ-TEV tag was purified using baculovirus expression in the same way as dynein described above - reference_id: PMID:36071160 supporting_text: Both adaptors make similar interactions with the dyneins but diverge in their contacts with each other and dynactin. references: - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt findings: [] - id: PMID:20360680 title: Pericentrosomal targeting of Rab6 secretory vesicles by Bicaudal-D-related protein 1 (BICDR-1) regulates neuritogenesis. findings: - statement: Mouse BICDR-1 binds GTP-bound Rab6A/B directly through its C-terminal domain; Lys-512 is required. supporting_text: showed that lysine 512 is required for binding to Rab6 - statement: BICDR-1 co-precipitates dynein/dynactin and recruits them to the pericentrosomal region. supporting_text: Overexpression of GFP-BICDR-1 caused an approximately two-fold increase in pericentrosomal dynein/dynactin fluorescent staining intensity - statement: BICDR-1 is required for the pericentrosomal clustering of Rab6 vesicles and shifts their transport to the minus-end direction. supporting_text: Together these data indicate that BICDR-1 localizes to Rab6-positive vesicles and required for the pericentrosomal distribution of Rab6 vesicles. - statement: BICDR-1 binds the KIF1C tail and recruits KIF1C to Rab6 vesicles. supporting_text: Here, we show that BICDR-1 does not interact with Kif5 but recruits kinesin-3/Kif1C to Rab6 secretory vesicles in hippocampal neurons. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Full text cached (PMC2876961). Primary characterisation of mouse BICDR-1; source of all GOA experimental rows. Cell work used mouse BICDR-1 constructs in HeLa, Vero and cultured hippocampal neurons; neurite phenotype is from sustained expression; the in vivo loss-of-function data are zebrafish morpholinos. - id: PMID:29420470 title: Cryo-EM shows how dynactin recruits two dyneins for faster movement. findings: - statement: Mouse BICDR1 preferentially recruits two dyneins to dynactin, producing faster and more forceful motility than BICD2. supporting_text: We conclude the majority of motile complexes containing BICD2 have one dynein, whereas both BICDR1 and HOOK3 preferentially recruit two. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Full text cached; methods state mouse BICDR1 (BICDL1) was used. Basis for the NEW cytoskeletal motor activator activity annotation. - id: PMID:36071160 title: Structure of dynein-dynactin on microtubules shows tandem adaptor binding. findings: - statement: Two full-length mouse BICDR1 molecules occupy the dynein-dynactin complex on microtubules. supporting_text: Both adaptors make similar interactions with the dyneins but diverge in their contacts with each other and dynactin. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Full text cached; methods state full-length mouse BICDR was purified. Basis for dynein complex binding. - id: PMID:33734450 title: Cryo-EM reveals the complex architecture of dynactin's shoulder region and pointed end. findings: - statement: BICDR1 contacts the dynactin pointed end. supporting_text: Extending our registry suggests that the positively charged site 1 loop on the pointed end binds to a negatively charged patch on BICDR1 reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Full text cached; structural refinement of dynactin with BICDR1; supports a direct dynactin interface. core_functions: - description: Activating adaptor for cytoplasmic dynein-1. BICDR-1 binds dynein and dynactin, recruits predominantly two dyneins per dynactin and activates fast processive minus-end-directed motility, while its C-terminal domain binds GTP-Rab6 on post-Golgi secretory vesicles, thereby moving Rab6 vesicles toward microtubule minus ends and concentrating them around the centrosome. molecular_function: id: GO:0140660 label: cytoskeletal motor activator activity directly_involved_in: - id: GO:0047496 label: vesicle transport along microtubule locations: - id: GO:0005813 label: centrosome supported_by: - reference_id: PMID:29420470 supporting_text: We conclude the majority of motile complexes containing BICD2 have one dynein, whereas both BICDR1 and HOOK3 preferentially recruit two. - reference_id: PMID:20360680 supporting_text: Together these data indicate that BICDR-1 localizes to Rab6-positive vesicles and required for the pericentrosomal distribution of Rab6 vesicles. - description: Rab6 effector. The C-terminal BICDL1/2-like domain binds GTP-bound Rab6A and Rab6B directly (Lys-512 required), linking the adaptor to its vesicle cargo. molecular_function: id: GO:0031267 label: small GTPase binding directly_involved_in: - id: GO:0047496 label: vesicle transport along microtubule supported_by: - reference_id: PMID:20360680 supporting_text: Binding of BICDR-1 to Rab6A is direct because the purified His-tagged C-terminus of BICDR-1 (amino acids 382–577) interacts with purified GST-Rab6A and GST-Rab6B and not with GST only suggested_questions: - question: Should coiled-coil dynein activating adaptors (BICD2, BICDR1, HOOK3) carry cytoskeletal motor activator activity (GO:0140660), given that current annotations of these adaptors use only dynein complex binding and dynactin binding? - question: Does endogenous BICDR-1 act on regulated dense-core secretory granules in neurons or neuroendocrine cells, or only on constitutive Rab6 exocytic carriers, which would decide whether Golgi to secretory granule transport is an appropriate process term? suggested_experiments: - description: Conditional Bicdl1 knockout in mouse cortical or hippocampal neurons, with live imaging of Rab6/NPY vesicles and neurite outgrowth, to obtain mammalian loss-of-function evidence (current mammalian neuronal data are from sustained expression, and in vivo loss-of-function data are from zebrafish morpholinos).