Summary: Ku70/Ku80 N-terminal alpha/beta domain
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Ku (protein) Edit Wikipedia article
|Locus||Chr. 2 q35|
|Alt. symbols||Ku70, G22P1|
|Locus||Chr. 22 q11-q13|
|Ku70/Ku80 N-terminal alpha/beta domain|
crystal structure of the ku heterodimer
|SCOPe||1jey / SUPFAM|
|Ku70/Ku80 beta-barrel domain|
crystal structure of the ku heterodimer bound to dna
|SCOPe||1jey / SUPFAM|
|Ku70/Ku80 C-terminal arm|
crystal structure of the ku heterodimer bound to dna
|SCOPe||1jey / SUPFAM|
|Ku C terminal domain like|
the 3d solution structure of the c-terminal region of ku86
|SCOPe||1q2z / SUPFAM|
Ku is a dimeric protein complex that binds to DNA double-strand break ends and is required for the non-homologous end joining (NHEJ) pathway of DNA repair. Ku is evolutionarily conserved from bacteria to humans. The ancestral bacterial Ku is a homodimer (two copies of the same protein bound to each other). Eukaryotic Ku is a heterodimer of two polypeptides, Ku70 (XRCC6) and Ku80 (XRCC5), so named because the molecular weight of the human Ku proteins is around 70 kDa and 80 kDa. The two Ku subunits form a basket-shaped structure that threads onto the DNA end. Once bound, Ku can slide down the DNA strand, allowing more Ku molecules to thread onto the end. In higher eukaryotes, Ku forms a complex with the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to form the full DNA-dependent protein kinase, DNA-PK. Ku is thought to function as a molecular scaffold to which other proteins involved in NHEJ can bind, orienting the double-strand break for ligation.
The Ku70 and Ku80 proteins consist of three structural domains. The N-terminal domain is an alpha/beta domain. This domain only makes a small contribution to the dimer interface. The domain comprises a six stranded beta sheet of the Rossman fold. The central domain of Ku70 and Ku80 is a DNA-binding beta-barrel domain. Ku makes only a few contacts with the sugar-phosphate backbone, and none with the DNA bases, but it fits sterically to major and minor groove contours forming a ring that encircles duplex DNA, cradling two full turns of the DNA molecule. By forming a bridge between the broken DNA ends, Ku acts to structurally support and align the DNA ends, to protect them from degradation, and to prevent promiscuous binding to unbroken DNA. Ku effectively aligns the DNA, while still allowing access of polymerases, nucleases and ligases to the broken DNA ends to promote end joining. The C-terminal arm is an alpha helical region which embraces the central beta-barrel domain of the opposite subunit. In some cases a fourth domain is present at the C-terminus, which binds to DNA-dependent protein kinase catalytic subunit.
Abundance of Ku80 seems to be related to species longevity.
Mutant mice defective in Ku70, or Ku80, or double mutant mice deficient in both Ku70 and Ku80 exhibit early aging. The mean lifespans of the three mutant mouse strains were similar to each other, at about 37 weeks, compared to 108 weeks for the wild-type control. Six specific signs of aging were examined, and the three mutant mice were found to display the same aging signs as the control mice, but at a much earlier age. Cancer incidence was not increased in the mutant mice. These results suggest that Ku function is important for longevity assurance and that the NHEJ pathway of DNA repair (mediated by Ku) has a key role in repairing DNA double-strand breaks that would otherwise cause early aging. (Also see DNA damage theory of aging.)
Ku70 and Ku80 have also been experimentally characterized in plants, where they appear to play a similar role to that in other eukaryotes. In rice, suppression of either protein has been shown to promote homologous recombination (HR) This effect was exploited to improve gene targeting (GT) efficiency in Arabidopsis thaliana. In the study, the frequency of HR-based GT using a zinc-finger nuclease (ZFN) was increased up to sixteen times in ku70 mutants This result has promising implications for genome editing across eukaryotes as DSB repair mechanisms are highly conserved. A substantial difference is that in plants, Ku is also involved in maintaining an alternate telomere morphology characterized by blunt-ends or short (â‰¤ 3-nt) 3â€™ overhangs. This function is independent of the role of Ku in DSB repair, as removing the ability of the Ku complex to translocate along DNA has been shown to preserve blunt-ended telomeres while impeding DNA repair.
The name 'Ku' is derived from the surname of the Japanese patient in which it was discovered.
- doi:10.1038/35088000. PMID 11493912. ; Walker JR, Corpina RA, Goldberg J (August 2001). "Structure of the Ku heterodimer bound to DNA and its implications for double-strand break repair". Nature. 412 (6847): 607â€“14.
- Doherty AJ, Jackson SP, Weller GR (July 2001). "Identification of bacterial homologues of the Ku DNA repair proteins". FEBS Lett. 500 (3): 186â€“8. doi:10.1016/S0014-5793(01)02589-3. PMID 11445083.
- Carter T, VancurovÃ¡ I, Sun I, Lou W, DeLeon S (December 1990). "A DNA-activated protein kinase from HeLa cell nuclei". Mol. Cell. Biol. 10 (12): 6460â€“71. doi:10.1128/MCB.10.12.6460. PMC 362923. PMID 2247066.
- Sugihara T, Wadhwa R, Kaul SC, Mitsui Y (April 1999). "A novel testis-specific metallothionein-like protein, tesmin, is an early marker of male germ cell differentiation". Genomics. 57 (1): 130â€“6. doi:10.1006/geno.1999.5756. PMID 10191092.
- Aravind L, Koonin EV (August 2001). "Prokaryotic homologs of the eukaryotic DNA-end-binding protein Ku, novel domains in the Ku protein and prediction of a prokaryotic double-strand break repair system". Genome Res. 11 (8): 1365â€“74. doi:10.1101/gr.181001. PMC 311082. PMID 11483577.
- Harris R, Esposito D, Sankar A, Maman JD, Hinks JA, Pearl LH, Driscoll PC (January 2004). "The 3D solution structure of the C-terminal region of Ku86 (Ku86CTR)". J. Mol. Biol. 335 (2): 573â€“82. doi:10.1016/j.jmb.2003.10.047. PMID 14672664.
- Difilippantonio MJ, Zhu J, Chen HT, Meffre E, Nussenzweig MC, Max EE, Ried T, Nussenzweig A (March 2000). "DNA repair protein Ku80 suppresses chromosomal aberrations and malignant transformation". Nature. 404 (6777): 510â€“4. doi:10.1038/35006670. PMC 4721590. PMID 10761921.
- Ferguson DO, Sekiguchi JM, Chang S, Frank KM, Gao Y, DePinho RA, Alt FW (June 2000). "The nonhomologous end-joining pathway of DNA repair is required for genomic stability and the suppression of translocations". Proc. Natl. Acad. Sci. U.S.A. 97 (12): 6630â€“3. doi:10.1073/pnas.110152897. PMC 18682. PMID 10823907.
- Boulton SJ, Jackson SP (March 1998). "Components of the Ku-dependent non-homologous end-joining pathway are involved in telomeric length maintenance and telomeric silencing". EMBO J. 17 (6): 1819â€“28. doi:10.1093/emboj/17.6.1819. PMC 1170529. PMID 9501103.
- Lorenzini A, Johnson FB, Oliver A, Tresini M, Smith JS, Hdeib M, Sell C, Cristofalo VJ, Stamato TD (Novâ€“Dec 2009). "Significant Correlation of Species Longevity with DNA Double Strand Break-Recognition but not with Telomere Length". Mech Ageing Dev. 130 (11â€“12): 784â€“92. doi:10.1016/j.mad.2009.10.004. PMC 2799038. PMID 19896964.
- Li H, Vogel H, Holcomb VB, Gu Y, Hasty P (2007). "Deletion of Ku70, Ku80, or both causes early aging without substantially increased cancer". Mol. Cell. Biol. 27 (23): 8205â€“14. doi:10.1128/MCB.00785-07. PMC 2169178. PMID 17875923.
- Bernstein H, Payne CM, Bernstein C, Garewal H, Dvorak K (2008). Cancer and aging as consequences of un-repaired DNA damage. In: New Research on DNA Damages (Editors: Honoka Kimura and Aoi Suzuki) Nova Science Publishers, Inc., New York, Chapter 1, pp. 1-47. open access, but read only https://www.novapublishers.com/catalog/product_info.php?products_id=43247 ISBN 978-1604565812
- Nishizawa-Yokoi A, Nonaka S, Saika H, Kwon YI, Osakabe K, Toki S (December 2012). "Suppression of Ku70/80 or Lig4 leads to decreased stable transformation and enhanced homologous recombination in rice". The New Phytologist. 196 (4): 1048â€“59. doi:10.1111/j.1469-8137.2012.04350.x. PMC 3532656. PMID 23050791.
- Qi Y, Zhang Y, Zhang F, Baller JA, Cleland SC, Ryu Y, Starker CG, Voytas DF (March 2013). "Increasing frequencies of site-specific mutagenesis and gene targeting in Arabidopsis by manipulating DNA repair pathways". Genome Research. 23 (3): 547â€“54. doi:10.1101/gr.145557.112. PMC 3589543. PMID 23282329.
- Kazda A, Zellinger B, RÃ¶ssler M, Derboven E, Kusenda B, Riha K (August 2012). "Chromosome end protection by blunt-ended telomeres". Genes & Development. 26 (15): 1703â€“13. doi:10.1101/gad.194944.112. PMC 3418588. PMID 22810623.
- Valuchova S, Fulnecek J, Prokop Z, Stolt-Bergner P, Janouskova E, Hofr C, Riha K (June 2017). "Protection of Arabidopsis Blunt-Ended Telomeres Is Mediated by a Physical Association with the Ku Heterodimer". The Plant Cell. 29 (6): 1533â€“1545. doi:10.1105/tpc.17.00064. PMC 5502450. PMID 28584163.
- Dynan, W.S. & Yoo, S. (1998) Nucleic Acids Research, 26 (7): 1551-1559. doi: 10.1093/nar/26.7.1551
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
Ku70/Ku80 N-terminal alpha/beta domain Provide feedback
The Ku heterodimer (composed of Ku70 P12956 and Ku80 P13010) contributes to genomic integrity through its ability to bind DNA double-strand breaks and facilitate repair by the non-homologous end-joining pathway. This is the amino terminal alpha/beta domain. This domain only makes a small contribution to the dimer interface. The domain comprises a six stranded beta sheet of the Rossman fold .
Aravind L, Koonin EV; , Genome Res 2001;11:1365-1374.: Prokaryotic homologs of the eukaryotic DNA-end-binding protein Ku, novel domains in the Ku protein and prediction of a prokaryotic double-strand break repair system. PUBMED:11483577 EPMC:11483577
Internal database links
|Similarity to PfamA using HHSearch:||VWA VWA_2|
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR005161
The Ku heterodimer (composed of Ku70 SWISSPROT and Ku80 SWISSPROT ) contributes to genomic integrity through its ability to bind DNA double-strand breaks and facilitate repair by the non-homologous end-joining pathway. This is the N-terminal alpha/beta domain. This domain only makes a small contribution to the dimer interface. The domain comprises a six stranded beta sheet of the Rossman fold [ PUBMED:10191092 ].
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
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|Seed source:||Bateman A|
|Number in seed:||12|
|Number in full:||3155|
|Average length of the domain:||206.10 aa|
|Average identity of full alignment:||19 %|
|Average coverage of the sequence by the domain:||31.01 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 57096847 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||17|
|Download:||download the raw HMM for this family|
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How the sunburst is generated
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Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
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The tree shows the occurrence of this domain across different species. More...
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For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
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For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Ku_N domain has been found. There are 42 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.
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AlphaFold Structure Predictions
The list of proteins below match this family and have AlphaFold predicted structures. Click on the protein accession to view the predicted structure.