3si5 | pdb_00003si5
Kinetochore-BUBR1 kinase complex
Structural highlights
Disease[BUB1B_HUMAN] Mosaic variegated aneuploidy syndrome. Defects in BUB1B are associated with tumor formation. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. MVA1 is caused by biallelic mutations in the BUB1B gene. [CASC5_HUMAN] Autosomal recessive primary microcephaly. A chromosomal aberration involving CASC5 is associated with acute myeloblastic leukemia (AML). Translocation t(11;15)(q23;q14) with KMT2A/MLL1. May give rise to a KMT2A/MLL1-CASC5 fusion protein. The disease is caused by mutations affecting the gene represented in this entry. Function[BUB1B_HUMAN] Essential component of the mitotic checkpoint. Required for normal mitosis progression. The mitotic checkpoint delays anaphase until all chromosomes are properly attached to the mitotic spindle. One of its checkpoint functions is to inhibit the activity of the anaphase-promoting complex/cyclosome (APC/C) by blocking the binding of CDC20 to APC/C, independently of its kinase activity. The other is to monitor kinetochore activities that depend on the kinetochore motor CENPE. Required for kinetochore localization of CENPE. Negatively regulates PLK1 activity in interphase cells and suppresses centrosome amplification. Also implicated in triggering apoptosis in polyploid cells that exit aberrantly from mitotic arrest. May play a role for tumor suppression.[1] [2] [3] [4] [5] [6] [CASC5_HUMAN] Performs two crucial functions during mitosis: it is essential for spindle-assembly checkpoint signaling and for correct chromosome alignment. Required for attachment of the kinetochores to the spindle microtubules. Directly links BUB1 and BUB1B to kinetochores. Part of the MIS12 complex, which may be fundamental for kinetochore formation and proper chromosome segregation during mitosis. Acts in coordination with CENPK to recruit the NDC80 complex to the outer kinetochore.[7] [8] [9] Publication Abstract from PubMedThe maintenance of genomic stability relies on the spindle assembly checkpoint (SAC), which ensures accurate chromosome segregation by delaying the onset of anaphase until all chromosomes are properly bioriented and attached to the mitotic spindle. BUB1 and BUBR1 kinases are central for this process and by interacting with Blinkin, link the SAC with the kinetochore, the macromolecular assembly that connects microtubules with centromeric DNA. Here, we identify the Blinkin motif critical for interaction with BUBR1, define the stoichiometry and affinity of the interaction, and present a 2.2 A resolution crystal structure of the complex. The structure defines an unanticipated BUBR1 region responsible for the interaction and reveals a novel Blinkin motif that undergoes a disorder-to-order transition upon ligand binding. We also show that substitution of several BUBR1 residues engaged in binding Blinkin leads to defects in the SAC, thus providing the first molecular details of the recognition mechanism underlying kinetochore-SAC signaling. Structure of a Blinkin-BUBR1 Complex Reveals an Interaction Crucial for Kinetochore-Mitotic Checkpoint Regulation via an Unanticipated Binding Site.,Bolanos-Garcia VM, Lischetti T, Matak-Vinkovic D, Cota E, Simpson PJ, Chirgadze DY, Spring DR, Robinson CV, Nilsson J, Blundell TL Structure. 2011 Oct 12. PMID:22000412[10] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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