id: A0A9L0JLY3 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, 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. The resulting complex is 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. 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 and limits neurite outgrowth early in neuronal differentiation. This donkey product (573 aa) is a non-canonical splice form of the donkey BICDL1 gene. It lacks a central coiled-coil exon that is present in human, mouse and the other donkey products, and it includes the alternative exon found in human isoform 2. The CC1 box and the C-terminal Rab6-binding region are both retained. existing_annotations: - 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. In this way it controls their microtubule-based traffic and their accumulation around the centrosome. action: ACCEPT reason: This is a TreeGrafter transfer within PANTHER subfamily PTHR32123:SF12 (BICD family-like cargo adapter 1). That subfamily also contains the experimentally characterised mouse Bicdl1/BICDR-1 (A0JNT9) and human BICDL1. The PAINT IBD for this term sits on the deuterostome node PTN001281025, so donkey falls inside the clade that inherited the function. Mouse BICDR-1 drives dynein-dependent traffic of Rab6/NPY secretory vesicles, which knockdown and overexpression experiments show. The benchmark donkey product keeps the CC1 box and the C-terminal Rab6-binding region, although it is an alternative splice form. The term describes 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: file:EQUAS/BICDL1/BICDL1-bioinformatics/human_Q6ZP65-uniprot.txt record_section: ["CC:FUNCTION"] supporting_text: Regulates the secretory vesicle transport by controlling the accumulation of Rab6-containing secretory vesicles in the pericentrosomal region - reference_id: file:EQUAS/BICDL1/BICDL1-bioinformatics/RESULTS-rereview.md supporting_text: It keeps the N-terminal CC1 box and the C-terminal region (the Rab6-binding region in mouse). - term: id: GO:0055107 label: Golgi to secretory granule transport evidence_type: IEA original_reference_id: GO_REF:0000118 qualifier: involved_in supporting_entities: - PANTHER:PTN001594046 review: summary: BICDL1 regulates the post-Golgi movement of Rab6/NPY-positive secretory carriers. Mostly it holds them near the centrosome instead of delivering them to the periphery. action: KEEP_AS_NON_CORE reason: A PAINT curator placed this term on node PTN001281025, using mouse Bicdl1 (MGI:1922915) as the seed, and donkey inherits it through SF12. 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. However, BICDR-1 mainly retains these vesicles in the pericentrosomal region and limits their anterograde secretory transport. Its role in Golgi-to-granule delivery is therefore 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 - 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: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. In in vitro reconstitution, BICDR1-dynein-dynactin complexes move processively, and about 94% of them contain two dyneins. This is the defining activity of the BICDR subfamily, and cytoskeletal motor activator activity is the term that fits it. Transfer is justified because donkey is in the same PANTHER subfamily (SF12) as mouse Bicdl1 and keeps the CC1 box, the dynein light-intermediate-chain binding motif that this activity needs. The central coiled-coil exon missing from this splice form may change the length of the adaptor. It does not remove the dynein-binding N-terminus. 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/BICDL1-bioinformatics/RESULTS.md supporting_text: 'MOTIF (CC1 box): human [113, 114, 115, 116, 117] AARLG -> donkey [114, 115, 116, 117, 118] AARLG.' references: - id: GO_REF:0000118 title: TreeGrafter-generated GO annotations 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 reference_review: relevance: HIGH correctness: VERIFIED review_notes: Primary characterisation of mouse BICDR-1 (full text cached from PMC). It is the source of the mouse experimental evidence behind the human ISS and PAINT annotations. - 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. It establishes the motor-activator activity of the subfamily. - id: file:EQUAS/BICDL1/BICDL1-uniprot.txt title: UniProt record for donkey BICDL1 (A0A9L0JLY3) 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/BICDL1-bioinformatics/human_Q6ZP65-uniprot.txt title: UniProt Swiss-Prot record for human BICDL1 (Q6ZP65) findings: - statement: The isoform-2 exon of human BICDL1 corresponds to the extra segment at donkey residues 389-436. record_section: ["FT:VAR_SEQ"] supporting_text: T -> TGSRRLDDDSLEEQIRQTSEDSRALRELMEGERGKLRQSLEELQRLH reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: The functional text of the human entry is itself transferred from mouse A0JNT9 (ECO:0000250). In the re-review, mouse primary literature (PMID:20360680) replaces it as the main support. It is kept for the isoform feature and the CC1 motif. - id: file:EQUAS/BICDL1/BICDL1-bioinformatics/RESULTS.md title: 'BICDL1: donkey-human sequence comparison' findings: - statement: Donkey and human BICDL1 are 96% identical over 524 aligned residues. Each has a segment of about 48 residues that has no counterpart in the other. supporting_text: The donkey sequence A0A9L0JLY3 (573 residues) aligns to human Q6ZP65 (573 residues) with 95.99% identity across 524 paired residues. - id: file:EQUAS/BICDL1/BICDL1-bioinformatics/RESULTS-rereview.md title: BICDL1 donkey gene-model comparison (re-review) findings: - statement: The benchmark product is a non-canonical transcript of donkey BICDL1. It is the only donkey model that lacks the central coiled-coil segment found in the human and mouse canonical sequences. supporting_text: The benchmark product is the only donkey model that lacks SEG_CORE. 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. - reference_id: PMID:20360680 supporting_text: specifically localized around the γ-tubulin-labelled centrosome - 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: Is the donkey BICDL1 splice form that skips the central coiled-coil exon and includes the isoform-2 exon (A0A9L0JLY3) actually expressed in donkey tissues? If so, does the changed coiled-coil length alter the spacing between the dynein-binding and Rab6-binding regions? suggested_experiments: - description: Run single-molecule motility assays with dynein-dynactin and recombinant donkey BICDL1, comparing the A0A9L0JLY3 splice form with the canonical-architecture product (A0A9L0K8K5 or A0A9L0I4K1). The aim is to test whether skipping the central coiled-coil exon changes dynein recruitment (one versus two dyneins) or velocity.