id: A0A9L0K8K5 gene_symbol: BICDL1 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9793 label: Equus asinus description: BICDL1 (BICD family-like cargo adaptor 1, also called BICDR-1) is a cytoplasmic coiled-coil activating adaptor for cytoplasmic dynein-1 and a member of the BICDR branch of the Spindly/BICDR dynein-adaptor family. Its N-terminal coiled coil, which carries a CC1 box, binds dynein and dynactin and assembles a processive minus-end-directed motor that usually contains two dynein dimers, which makes it faster than complexes formed with BICD2. The N-terminal region also binds the kinesin-3 KIF1C, and the C-terminal region binds the GTP-bound forms of the Golgi and secretory-vesicle GTPases RAB6A and RAB6B. Through these interactions BICDL1 concentrates Rab6-positive secretory vesicles in the pericentrosomal region, which restricts their anterograde delivery in young neurons. This donkey product (626 aa) is the translation of the Ensembl canonical transcript of the donkey BICDL1 gene. It keeps the full canonical coiled-coil architecture of mouse and human BICDL1, including the CC1 box and the lysine needed for Rab6 binding, and also includes the alternative exon found in human isoform 2. All of its functions are inferred from the mouse and human orthologs; none has been tested on the donkey protein. existing_annotations: - term: id: GO:0005813 label: centrosome evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in supporting_entities: - UniProtKB:A0JNT9 - ensembl:ENSMUSP00000053547 review: summary: Mouse BICDR-1 and its Rab6 vesicle cargo collect around the centrosome. This localization depends on dynein-dynactin and on microtubules. action: ACCEPT reason: This is an Ensembl Compara transfer from the one-to-one mouse ortholog Bicdl1 (A0JNT9), which is in the same PANTHER subfamily (PTHR32123:SF12) as the donkey product. Endogenous mouse BICDR-1 localizes around the gamma-tubulin-labelled centrosome, and loses that localization when dynein or dynactin is depleted. The protein is pericentrosomal rather than centriolar, and the centrosome term includes the pericentriolar material. The pericentrosomal position is where the adaptor holds its vesicle cargo, so it is the location of its core function. The donkey protein keeps the CC1 box and the C-terminal Rab6 binding region on which this localization depends. 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 (Figure 3F). - reference_id: PMID:20360680 supporting_text: Quantification showed that only ∼15% of the dynein/dynactin knockdown cells showed BICDR-1 around the centrosome compared with ∼74% in control cells (Figure 4C). - term: id: GO:0031175 label: neuron projection development evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in supporting_entities: - UniProtKB:A0JNT9 - ensembl:ENSMUSP00000053547 review: summary: In cultured rat hippocampal neurons, sustained BICDR-1 expression reduces neurite outgrowth by holding Rab6 secretory vesicles in the soma. BICDL1 does not itself carry out neurite development. action: MARK_AS_OVER_ANNOTATED reason: The mouse source annotation rests on a cellular phenotype. Overexpression of BICDR-1, or of its Rab6-binding domain, in cultured neurons shortens neurites because Rab6 vesicles are retained around the centrosome and fewer reach the neurites. That makes BICDR-1 an indirect, negative influence on neurite growth, acting through its vesicle-transport function, and the evidence is from overexpression. The positive process term misstates that relationship. PAINT curators propagated the vesicle-transport terms from the same mouse seed to node PTN001281025 but did not propagate this term, which is consistent with treating it as downstream of the core function. It is not removed, because the vesicle positioning that BICDR-1 performs does influence neurite outgrowth. 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 (Figure 8A and B). - 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: IEA original_reference_id: GO_REF:0000107 qualifier: enables supporting_entities: - UniProtKB:A0JNT9 - ensembl:ENSMUSP00000053547 review: summary: BICDL1 is a Rab6 effector. Its C-terminal region binds the GTP-bound forms of RAB6A and RAB6B, and this binding attaches the adaptor to its vesicle cargo. action: ACCEPT reason: In mouse, both full-length BICDR-1 and its C-terminal region bind constitutively active Rab6A but not GDP-locked Rab6A, and Lys512 is required for the binding. Without Rab6A, BICDR-1 is lost from the pericentrosomal region, so Rab6 binding is how the adaptor recognises its cargo. The donkey product keeps the corresponding lysine (donkey Lys562, in an identical context) and the C-terminal BICDL1/2-like domain, and it is in the same PANTHER subfamily (SF12) as mouse Bicdl1. PAINT did not place a binding term at the deuterostome node, but that omission concerns the deep node; this row is a one-to-one transfer between two mammals with conserved binding residues. No Rab-specific GO term is available, so small GTPase binding is the appropriate term. supported_by: - 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: GST-Rab6 pull-down assays with lysates of cells expressing mutant BICDR-1-K512M and an in vitro binding assay using purified His-BICDR-1C-K512M showed that lysine 512 is required for binding to Rab6 (Figure 3C). - reference_id: file:EQUAS/BICDL1__A0A9L0K8K5/BICDL1__A0A9L0K8K5-bioinformatics/RESULTS.md supporting_text: Mouse Lys512, required for Rab6 binding in mouse BICDR-1, aligns to donkey Lys562, in an identical 11-residue context (DAIQQKLNLSQ). - term: id: GO:0034452 label: dynactin binding evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: enables supporting_entities: - UniProtKB:A0JNT9 - ensembl:ENSMUSP00000053547 review: summary: BICDL1 binds dynactin through its N-terminal coiled coil, which lies along the dynactin filament in the dynein-dynactin-BICDR1 complex. action: ACCEPT reason: Mouse BICDR-1 co-immunoprecipitates the major dynein and dynactin subunits, and endogenous BICDR-1 co-localizes with dynactin around the centrosome. In the cryo-EM structure of the dynein tail-dynactin-BICDR1 complex, the BICDR1 coiled coil (residues 105-392) was modelled on dynactin, which shows that the binding is direct. Dynactin binding is the part of the adaptor mechanism that this term captures; the activity that results is captured by cytoskeletal motor activator activity (proposed as NEW). The donkey product is in SF12 and keeps the CC1 box and the N-terminal coiled coil. 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 (Figure 4A). - reference_id: PMID:29420470 supporting_text: An approximate model for the BICDR1 coiled coil (residues 105-392) was generated by placing helices into density - term: id: GO:0047496 label: vesicle transport along microtubule evidence_type: IEA original_reference_id: GO_REF:0000118 qualifier: involved_in supporting_entities: - PANTHER:PTN001594046 review: summary: BICDL1 recruits dynein-dynactin and KIF1C to Rab6-positive secretory vesicles, and so controls their microtubule-based traffic and their accumulation around the centrosome. action: ACCEPT reason: This is a TreeGrafter transfer within PANTHER subfamily PTHR32123:SF12. The PAINT IBD for this term sits on the deuterostome node PTN001281025, seeded by zebrafish bicdl1, so donkey falls inside the clade that inherited the function. Mouse BICDR-1 drives dynein-dependent traffic of Rab6/NPY secretory vesicles and accelerates their minus-end-directed movement. As the motor adaptor on the vesicle, BICDL1 performs part of the transport itself. This is the core process. supported_by: - reference_id: PMID:20360680 supporting_text: Here, we show that BICDR-1 is a Rab6 effector, recruits dynein/dynactin and Kif1C to Rab6/NPY-positive secretory vesicles and controls the trafficking and distribution of these carriers. - reference_id: PMID:25176647 supporting_text: BICD-related protein 1 (BICDR-1) accelerates minus-end-directed vesicle movements and affects Rab6 vesicle distribution. - term: id: GO:0055107 label: Golgi to secretory granule transport evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: involved_in supporting_entities: - UniProtKB:A0JNT9 - ensembl:ENSMUSP00000053547 - PANTHER:PTN001594046 review: summary: BICDL1 regulates the post-Golgi movement of Rab6/NPY-positive secretory carriers, mostly by holding them near the centrosome rather than delivering them to the periphery. action: KEEP_AS_NON_CORE reason: A PAINT curator placed this term on node PTN001281025 with mouse Bicdl1 (MGI:1922915) as the seed, and donkey inherits it through SF12; the Ensembl Compara transfer from mouse agrees. The carriers that BICDR-1 controls contain Rab6 and NPY-GFP, and NPY is a dense-core secretory cargo, so the term's cargo is a reasonable fit. BICDR-1 mainly retains these vesicles in the pericentrosomal region, though, and limits their anterograde secretory transport, so its role in Golgi-to-granule delivery is regulatory and depends on context. The more general vesicle-transport-along-microtubule term is the core process. This term is kept as true but non-core, in deference to the IBD. supported_by: - reference_id: PMID:20360680 supporting_text: Hela cells co-transfected with mCherry-BICDR-1 and NPY-GFP and stained for endogenous Rab6A showed that most of the centrosomal BICDR-1-positive vesicles contain NPY-GFP - term: id: GO:0140660 label: cytoskeletal motor activator activity evidence_type: ISS original_reference_id: PMID:29420470 qualifier: enables review: summary: As an activating adaptor, BICDL1 turns dynein-dynactin into a processive motor. Because it preferentially recruits two dyneins, the motor is faster and generates more force. action: NEW reason: The donkey GOA record has no molecular function apart from two binding terms. In in vitro reconstitution, BICDR1-dynein-dynactin complexes move processively, and about 94% contain two dyneins. This is the defining activity of the BICDR subfamily, and cytoskeletal motor activator activity ("binds to and increases the activity of a motor protein") is the term that fits. BICDL1 does the activating work itself, so this is participation rather than requirement. Transfer is justified because donkey is in the same PANTHER subfamily (SF12) as the characterised mouse and human proteins and keeps the CC1 box and the full N-terminal coiled coil that binds dynein and dynactin. The activity has not been measured for the donkey protein. 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: This arrangement results in a dynein/dynactin complex that moves faster and can produce larger forces. - reference_id: file:EQUAS/BICDL1__A0A9L0K8K5/BICDL1__A0A9L0K8K5-bioinformatics/RESULTS.md supporting_text: 'CC1 box (AARLG), the dynein light-intermediate-chain binding motif of activating adaptors: donkey 114, mouse 116, human 113.' references: - id: GO_REF:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara findings: [] - id: GO_REF:0000118 title: TreeGrafter-generated GO annotations findings: [] - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods 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 is a Rab6 effector that recruits dynein/dynactin and Kif1C to Rab6/NPY secretory vesicles and keeps them in the pericentrosomal region. supporting_text: BICDR-1 interacts with Rab6, Kif1C and the dynein/dynactin motor complex, and coordinates trafficking of Rab6/NPY-positive secretory vesicles. - statement: Kif1C binds the N-terminal region of BICDR-1. 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 - statement: Lys512 of mouse BICDR-1 is required for Rab6 binding. supporting_text: showed that lysine 512 is required for binding to Rab6 reference_review: relevance: HIGH correctness: VERIFIED review_notes: Primary characterisation of mouse BICDR-1 (full text cached). It is the source of the mouse experimental evidence behind the Ensembl Compara transfers and the PAINT seed MGI:1922915. - id: PMID:29420470 title: Cryo-EM shows how dynactin recruits two dyneins for faster movement. findings: - statement: BICDR1 preferentially recruits two dyneins to dynactin, which produces faster movement than with 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: In vitro reconstitution and cryo-EM of a BICDR1-dynein-dynactin complex (full text cached). It establishes the motor-activator activity of the subfamily and the direct contact of the BICDR1 coiled coil with dynactin. - id: PMID:25176647 title: Bicaudal d family adaptor proteins control the velocity of Dynein-based movements. findings: - statement: BICDR-1 accelerates dynein-driven, minus-end-directed movement of Rab6 vesicles in cells. supporting_text: BICD-related protein 1 (BICDR-1) accelerates minus-end-directed vesicle movements and affects Rab6 vesicle distribution. reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Abstract only in the cache. Corroborates the cell-based effect of BICDR-1 on dynein velocity. - id: PMID:42774019 title: A mutation in Bicdl1 (BICD family-like cargo adaptor 1) leads to mild outer retina thinning and late retinal dysfunction in a mouse model. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Mouse knock-in point mutant with a mild organismal retinal phenotype. Not used as support for any annotation, because the phenotype is downstream and does not identify a process BICDL1 performs. - id: file:EQUAS/BICDL1__A0A9L0K8K5/BICDL1__A0A9L0K8K5-uniprot.txt title: UniProt record for donkey BICDL1 (A0A9L0K8K5) findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Unreviewed TrEMBL entry, PE 4. Used for its sequence and its PANTHER SF12 and Pfam classification. It contains no curated functional text. - id: file:EQUAS/BICDL1__A0A9L0K8K5/BICDL1__A0A9L0K8K5-bioinformatics/RESULTS.md title: 'BICDL1 (donkey A0A9L0K8K5): comparison with mouse and human orthologs' findings: - statement: Donkey A0A9L0K8K5 is 95% identical to mouse Bicdl1 over aligned residues, keeps the CC1 box and the Rab6-binding lysine, and has one isoform-2-type insertion. supporting_text: 'Donkey vs mouse A0JNT9: 545 identical of 574 aligned pairs (94.95% identity over aligned residues); 52 donkey residues unaligned.' core_functions: - description: Activating adaptor that links cytoplasmic dynein-dynactin to Rab6-positive secretory vesicles. It activates processive minus-end motility by recruiting two dyneins, and it concentrates the vesicles 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: Here, we show that BICDR-1 is a Rab6 effector, recruits dynein/dynactin and Kif1C to Rab6/NPY-positive secretory vesicles and controls the trafficking and distribution of these carriers. - description: Rab6 effector that binds GTP-bound Rab6 through its C-terminal region and so attaches the dynein adaptor to its secretory 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: 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 suggested_questions: - question: Does the isoform-2-type exon present in this donkey product (residues 442-489, between the dynein-binding and Rab6-binding regions) change how BICDL1 engages dynein-dynactin or Rab6, and is it the predominant donkey transcript in vivo? suggested_experiments: - description: Reconstitute dynein-dynactin with recombinant donkey BICDL1 (A0A9L0K8K5) and a variant lacking residues 442-489, and compare single-molecule velocity, run length and the fraction of complexes with two dyneins. This would test the inferred motor-activator activity directly in the donkey protein.