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Data show how KNL1 binds both PP1 and microtubules. Unexpectedly, PP1 and microtubules bind KNL1 via overlapping binding sites. Co-sedimentation assays unequivocally demonstrated that microtubules and PP1 binding to KNL1 is mutually exclusive, with preferential formation of the KNL1:PP1 holoenzyme in the presence of PP1.
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Study demonstrates that KNL1 acts as a receptor of linear ubiquitin chains to anchor CENP-E at attached kinetochores. Thus, linear ubiquitin chains constitute a critical mechanism for chromosome congression and alignment by coupling the dynamic kinetochore microtubule motor CENP-E to the static one, the KMN network.
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Mutations in the CASC5 gene were found to encode a kinetochore protein essential for mitotic cell division and to cause autosomal recessive primary microcephaly 4. (Review)
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Therefore, Mps1 promotes checkpoint activation through sequentially phosphorylating Knl1, Bub1, and Mad1. This sequential multi-target phosphorylation cascade makes the checkpoint highly responsive to Mps1 and to kinetochore-microtubule attachment.
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CASC5 may contribute to the morphological and structural changes of the human brain during recent evolution. The observed between-population divergence of CASC5 variants was driven by natural selection that tends to favor a larger gray matter volume in East Asians.
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Involvement of CASC5 in autosomal recessive microcephaly and a founder effect of the c.6125G>A mutation.
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Targeted Knockdown of the Kinetochore Protein D40/Knl-1 Inhibits Human Cancer in a p53 Status-Independent Manner
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We propose that CASC5 has a key role for the correct functioning of DNA damage response proteins, and a defect in this connection might affect upstream and downstream DNA damage response events as response to increased genotoxic stress.
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Data show sequential multisite regulation of the microtubule-associated protein KNL1-kinase-adaptor complex BUB1/BUB3 interaction.
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Mechanisms of mitosis-specific assembly of the checkpoint platform Knl1/MIS12/NDC80 at human kinetochores.
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PP2A-B56 is a key phosphatase for the removal of the Mps1-mediated Knl1 phosphorylations necessary for Bub1/BubR1 recruitment in mammalian cells.
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Protein phosphatase 1 (PP1) binding to KNL1 during prometaphase reduces the levels of Bub proteins at kinetochores to approximately the level recruited by four active MELT repeats.
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In cells depleted of endogenous Knl1, kinetochore-targeted Knl1(1-250) suffices to restore spindle assembly checkpoint and chromosome alignment
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KNL1 contains an extensive array of short linear sequence modules that encompass TxxOmega and MELT motifs and that can independently localize BUB1.
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KNL1 is a requirement for Aurora B activity at kinetochores and for wild-type kinetochore-MT attachment dynamics.
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Data provide strong evidence for CASC5 as a novel MCPH gene, and underscore the role of kinetochore integrity in proper volumetric development of the human brain.
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we identify the Blinkin motif critical for interaction with BUBR1, define the stoichiometry and affinity of the interaction, and present a 2.2 Angstrom resolution crystal structure of the complex
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Expression levels of D40 mRNA and proteins decrease according to the degree of spermatogenesis impairment in male infertile patients.
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h-KNL1 functions to connect Bub1 and BubR1 with the hMis12, Ndc80, and Zwint-1 complexes.
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phosphorylation of KNL1 by Aurora B disrupts the KNL1-PP1 interaction