Gene Ontology annotation through association of InterPro records with GO terms
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
Electronic Gene Ontology annotations created by transferring manual GO annotations between related proteins based on shared sequence features
Combined Automated Annotation using Multiple IEA Methods
Spindly, a novel protein essential for silencing the spindle assembly checkpoint, recruits dynein to the kinetochore.
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Spindly was discovered as a kinetochore protein required for dynein recruitment and SAC silencing in Drosophila; a human homologue was identified with similar function.
"After the depletion of Spindly, dynein cannot target to kinetochores, and, as a result, cells arrest in metaphase with high levels of kinetochore-bound Mad2 and RZZ"
Mitotic control of kinetochore-associated dynein and spindle orientation by human Spindly.
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Human Spindly localizes to the outer kinetochore via the RZZ complex, recruits dynein-dynactin, and is required for chromosome alignment and spindle orientation. Unlike Drosophila, human Spindly is not required for checkpoint protein stripping from kinetochores.
"hSpindly depletion results in reduced inter-KT tension, unstable KT fibers, an extensive prometaphase delay, and severe chromosome misalignment...depletion of hSpindly induces a striking spindle rotation, which can be rescued by co-depletion of dynein...in contrast to Drosophila, hSpindly depletion does not abolish the removal of MAD2 and ZW10 from KTs"
A high-confidence interaction map identifies SIRT1 as a mediator of acetylation of USP22 and the SAGA coactivator complex.
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SPDL1 was identified as a SIRT1-interacting protein in a high-throughput interaction screen. The biological significance of this interaction for Spindly function is unclear.
"a comprehensive analysis of SIRT1 binding proteins yielding a high-confidence interaction map"
Activation of cytoplasmic dynein motility by dynactin-cargo adapter complexes.
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Spindly functions as a cargo adaptor that links the dynein motor complex to various cargos and converts dynein from a non-processive to a highly processive motor in the presence of dynactin.
"Recombinant SNAPf-tagged Rab11-FIP3, human Spindly, and Hook3 (fig"
A proteome-scale map of the human interactome network.
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Large-scale yeast two-hybrid interactome study detecting SPDL1 interactions with multiple partners including CA8, DNAAF4, PPP1R18, RTP5, TRAF4, USP15.
"A proteome-scale map of the human interactome network"
Widespread macromolecular interaction perturbations in human genetic disorders.
Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing.
USP45 and Spindly are part of the same complex implicated in cell migration.
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USP45 and Spindly form a complex; Spindly is monoubiquitinated and deubiquitinated by USP45; both play roles in cell migration.
"Here, we also show that Spindly is mono-ubiquitylated and this can be specifically removed by USP45 in its active form but not by the catalytic inactive form"
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
Removal of Spindly from microtubule-attached kinetochores controls spindle checkpoint silencing in human cells.
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Dynein-mediated removal of Spindly from microtubule-attached kinetochores is the critical reaction in checkpoint silencing. A conserved Spindly motif is essential for dynein targeting to kinetochores.
"we identify a conserved motif in Spindly that is essential for kinetochore targeting of dynein"
Dynamic kinetochore size regulation promotes microtubule capture and chromosome biorientation in mitosis.
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Spindly and RZZ drive kinetochore corona expansion in a dynein-independent manner. C-terminal farnesylation and MPS1 kinase activity cause Spindly conformational changes promoting oligomerization of RZZ-Spindly complexes.
"the dynein adaptor Spindly and the RZZ (ROD-Zwilch-ZW10) complex drive kinetochore expansion in a dynein-independent manner"
BioReason deep research on SPDL1 (Spindly)
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BioReason analysis correctly identifies the dynein-adapter core architecture and kinetochore adaptor function. Contains some errors regarding specific binding partners (BUB1B, NDC80, SKA, CENP-F, HOX-D13, MKLN1) that are not supported by published literature.
Falcon (Edison) deep research on human SPDL1 (Spindly, Q96EA4)
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Spindly is a coiled-coil activating adaptor that links the minus-end motor cytoplasmic dynein-1 and its cofactor dynactin to the kinetochore fibrous corona during mitosis, enabling dynein recruitment and activation at kinetochores.
"links the microtubule minus-end motor **cytoplasmic dynein-1** and its cofactor **dynactin** to the **kinetochore fibrous corona** during mitosis, enabling dynein recruitment/activation at kinetochores"
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Spindly operates within the RZZ-Spindly pathway to recruit dynein-dynactin to the fibrous corona and to promote dynein-dependent poleward stripping of corona material, contributing to SAC silencing.
"Spindly operates within the **RZZ–Spindly pathway** to recruit dynein–dynactin to this region and to promote **dynein-dependent “stripping”** (poleward transport/removal) of corona material"
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Domain architecture: a CC1 box creates a binding pocket for a conserved amphipathic helix in dynein LIC; the Spindly motif engages the dynactin pointed-end; a C-terminal CAAX motif enables farnesylation.
"**Spindly motif**: contributes to interaction with the **dynactin pointed-end**."
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Spindly is recruited to kinetochores via the RZZ complex (ROD-ZW10-ZWILCH) and C-terminal farnesylation, with the Rod beta-propeller acting as a farnesyl receptor in humans.
"Spindly is recruited to kinetochores primarily through the **RZZ complex** (ROD–ZW10–ZWILCH). A key targeting mechanism is **C-terminal farnesylation**, with the **Rod β-propeller** acting as a **farnesyl receptor** in humans"
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Full-length Spindly is autoinhibited, adopting a closed conformation that occludes the CC1 box and Spindly motif and prevents productive dynein-dynactin binding in solution until activated at kinetochores.
"full-length Spindly is autoinhibited"
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Updated 2023 model (Ide et al.): the checkpoint-silencing role of kinetochore dynein recruited via Spindly is restricted primarily to disassembly of the fibrous corona rather than wholesale removal of all outer-kinetochore checkpoint proteins.
"kinetochore dynein’s checkpoint-silencing role is **restricted primarily to disassembly of the fibrous corona**, rather than wholesale removal of checkpoint proteins from the entire outer kinetochore"
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Localization is cell-cycle dependent: nuclear in interphase, kinetochore in prometaphase, relocalizing toward spindle poles before metaphase, and lost after chromosome congression.
"**Prometaphase:** kinetochore localization."
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A rare SPDL1 missense variant p.Arg20Gln (rs116483731) is associated with idiopathic pulmonary fibrosis, and shows antagonistic pleiotropy with increased IPF risk but decreased cancer risk.
"the same SPDL1 missense allele shows **antagonistic pleiotropy**: increased IPF risk but decreased cancer risk"
MAD2 converted to an inhibitory state via interaction with Mad1
MAD2 associates with the Mad1 kinetochore complex
Release of activated MAD2 from kinetochores
Phosphorylation of cohesin by PLK1 at centromeres
PP2A-B56 dephosphorylates centromeric cohesin
ESPL1 (Separase) cleaves centromeric cohesin
Separation of sister chromatids
CDK1 phosphorylates CDCA5 (Sororin) at centromeres
Kinetochore capture of astral microtubules
CDC42:GTP recruits DIAPH2-2 to kinetochores
AURKB phosphorylates DIAPH2-2 at kinetochores
Kinetochore capture of astral microtubules is positively regulated by CDC42:GTP:p-S196-DIAPH2-2
EML4 recruits NUDC to mitotic spindle