| Structural highlights
Disease
[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
[BUB1_HUMAN] Serine/threonine-protein kinase that performs 2 crucial functions during mitosis: it is essential for spindle-assembly checkpoint signaling and for correct chromosome alignment. Has a key role in the assembly of checkpoint proteins at the kinetochore, being required for the subsequent localization of CENPF, BUB1B, CENPE and MAD2L1. Required for the kinetochore localization of PLK1. Plays an important role in defining SGOL1 localization and thereby affects sister chromatid cohesion. Acts as a substrate for anaphase-promoting complex or cyclosome (APC/C) in complex with its activator CDH1 (APC/C-Cdh1). Necessary for ensuring proper chromosome segregation and binding to BUB3 is essential for this function. Can regulate chromosome segregation in a kinetochore-independent manner. Can phosphorylate BUB3. The BUB1-BUB3 complex plays a role in the inhibition of APC/C when spindle-assembly checkpoint is activated and inhibits the ubiquitin ligase activity of APC/C by phosphorylating its activator CDC20. This complex can also phosphorylate MAD1L1. Kinase activity is essential for inhibition of APC/CCDC20 and for chromosome alignment but does not play a major role in the spindle-assembly checkpoint activity. Mediates cell death in response to chromosome missegregation and acts to suppress spontaneous tumorigenesis.[1] [2] [3] [4] [5] [6] [7] [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.[8] [9] [10]
Publication Abstract from PubMed
The function of the essential checkpoint kinases Bub1 and BubR1 requires their recruitment to mitotic kinetochores. Kinetochore recruitment of Bub1 and BubR1 is proposed to rely on the interaction of the tetratricopeptide repeats (TPRs) of Bub1 and BubR1 with two KI motifs in the outer kinetochore protein Knl1. We determined the crystal structure of the Bub1 TPRs in complex with the cognate Knl1 KI motif and compared it with the structure of the equivalent BubR1TPR-KI motif complex. The interaction developed along the convex surface of the TPR assembly. Point mutations on this surface impaired the interaction of Bub1 and BubR1 with Knl1 in vitro and in vivo but did not cause significant displacement of Bub1 and BubR1 from kinetochores. Conversely, a 62-residue segment of Bub1 that includes a binding domain for the checkpoint protein Bub3 and is C terminal to the TPRs was necessary and largely sufficient for kinetochore recruitment of Bub1. These results shed light on the determinants of kinetochore recruitment of Bub1.
Structural analysis reveals features of the spindle checkpoint kinase Bub1-kinetochore subunit Knl1 interaction.,Krenn V, Wehenkel A, Li X, Santaguida S, Musacchio A J Cell Biol. 2012 Feb 20;196(4):451-67. Epub 2012 Feb 13. PMID:22331848[11]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Seeley TW, Wang L, Zhen JY. Phosphorylation of human MAD1 by the BUB1 kinase in vitro. Biochem Biophys Res Commun. 1999 Apr 13;257(2):589-95. PMID:10198256 doi:http://dx.doi.org/S0006-291X(99)90514-4
- ↑ Johnson VL, Scott MI, Holt SV, Hussein D, Taylor SS. Bub1 is required for kinetochore localization of BubR1, Cenp-E, Cenp-F and Mad2, and chromosome congression. J Cell Sci. 2004 Mar 15;117(Pt 8):1577-89. PMID:15020684 doi:http://dx.doi.org/10.1242/jcs.01006
- ↑ Tang Z, Shu H, Oncel D, Chen S, Yu H. Phosphorylation of Cdc20 by Bub1 provides a catalytic mechanism for APC/C inhibition by the spindle checkpoint. Mol Cell. 2004 Nov 5;16(3):387-97. PMID:15525512 doi:http://dx.doi.org/10.1016/j.molcel.2004.09.031
- ↑ Kitajima TS, Hauf S, Ohsugi M, Yamamoto T, Watanabe Y. Human Bub1 defines the persistent cohesion site along the mitotic chromosome by affecting Shugoshin localization. Curr Biol. 2005 Feb 22;15(4):353-9. PMID:15723797 doi:http://dx.doi.org/S0960982204010267
- ↑ Qi W, Tang Z, Yu H. Phosphorylation- and polo-box-dependent binding of Plk1 to Bub1 is required for the kinetochore localization of Plk1. Mol Biol Cell. 2006 Aug;17(8):3705-16. Epub 2006 Jun 7. PMID:16760428 doi:http://dx.doi.org/10.1091/mbc.E06-03-0240
- ↑ Qi W, Yu H. KEN-box-dependent degradation of the Bub1 spindle checkpoint kinase by the anaphase-promoting complex/cyclosome. J Biol Chem. 2007 Feb 9;282(6):3672-9. Epub 2006 Dec 11. PMID:17158872 doi:http://dx.doi.org/10.1074/jbc.M609376200
- ↑ Klebig C, Korinth D, Meraldi P. Bub1 regulates chromosome segregation in a kinetochore-independent manner. J Cell Biol. 2009 Jun 1;185(5):841-58. doi: 10.1083/jcb.200902128. PMID:19487456 doi:http://dx.doi.org/10.1083/jcb.200902128
- ↑ Obuse C, Iwasaki O, Kiyomitsu T, Goshima G, Toyoda Y, Yanagida M. A conserved Mis12 centromere complex is linked to heterochromatic HP1 and outer kinetochore protein Zwint-1. Nat Cell Biol. 2004 Nov;6(11):1135-41. Epub 2004 Oct 24. PMID:15502821 doi:http://dx.doi.org/10.1038/ncb1187
- ↑ Kiyomitsu T, Obuse C, Yanagida M. Human Blinkin/AF15q14 is required for chromosome alignment and the mitotic checkpoint through direct interaction with Bub1 and BubR1. Dev Cell. 2007 Nov;13(5):663-76. PMID:17981135 doi:http://dx.doi.org/10.1016/j.devcel.2007.09.005
- ↑ Cheeseman IM, Hori T, Fukagawa T, Desai A. KNL1 and the CENP-H/I/K complex coordinately direct kinetochore assembly in vertebrates. Mol Biol Cell. 2008 Feb;19(2):587-94. Epub 2007 Nov 28. PMID:18045986 doi:http://dx.doi.org/10.1091/mbc.E07-10-1051
- ↑ Krenn V, Wehenkel A, Li X, Santaguida S, Musacchio A. Structural analysis reveals features of the spindle checkpoint kinase Bub1-kinetochore subunit Knl1 interaction. J Cell Biol. 2012 Feb 20;196(4):451-67. Epub 2012 Feb 13. PMID:22331848 doi:10.1083/jcb.201110013
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