Summary: BRCA2, oligonucleotide/oligosaccharide-binding, domain 1
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BRCA2 Edit Wikipedia article
|Breast cancer 2, early onset|
PDB rendering based on 1n0w.
|RNA expression pattern|
crystal structure of a rad51-brca2 brc repeat complex
structure of a brca2-dss1 complex
|BRCA2, oligonucleotide/oligosaccharide-binding, domain 1|
structure of a brca2-dss1 complex
|BRCA2, oligonucleotide/oligosaccharide-binding, domain 3|
structure of a brca2-dss1 complex
structure of a brca2-dss1 complex
BRCA2 and BRCA2 (//) are a human gene and its protein product, respectively. The official symbol (BRCA2, italic for the gene, nonitalic for the protein) and the official name (breast cancer 2, early onset) are maintained by the HGNC. Orthologs, styled Brca2 and Brca2, are common in other mammal species. BRCA2 is a human tumor suppressor gene (specifically, a caretaker gene), found in all humans; its protein, also called by the synonym breast cancer type 2 susceptibility protein, is responsible for repairing DNA.
BRCA2 and BRCA1 are normally expressed in the cells of breast and other tissue, where they help repair damaged DNA or destroy cells if DNA cannot be repaired. They are involved in the repair of chromosomal damage with an important role in the error-free repair of DNA double strand breaks. If BRCA1 or BRCA2 itself is damaged by a BRCA mutation, damaged DNA is not repaired properly, and this increases the risk for breast cancer. Thus, although the terms "breast cancer susceptibility gene" and "breast cancer susceptibility protein" (used frequently both in and outside the medical literature) sound as if they describe a proto-oncogene or oncogene, BRCA1 and BRCA2 are "normal"; it is their mutation that is abnormal.
The BRCA2 gene is located on the long (q) arm of chromosome 13 at position 12.3 (13q12.3). The human reference BRCA 2 gene contains 27 exons, and the cDNA has 10,254 base pairs coding for a protein of 3418 amino acids.
Methods to diagnose the likelihood of a patient with mutations in BRCA1 and BRCA2 getting cancer were covered by patents owned or controlled by Myriad Genetics. Myriad's business model of exclusively offering the diagnostic test led from Myriad being a startup in 1994 to being a publicly traded company with 1200 employees and about $500M in annual revenue in 2012; it also led to controversy over high prices and the inability to get second opinions from other diagnostic labs, which in turn led to the landmark Association for Molecular Pathology v. Myriad Genetics lawsuit.
Although the structures of the BRCA1 and BRCA2 genes are very different, at least some functions are interrelated. The proteins made by both genes are essential for repairing damaged DNA. BRCA2 binds the single strand DNA and directly interacts with the recombinase RAD51 to stimulate strand invasion a vital step of homologous recombination. The localization of RAD51 to the DNA double-strand break requires the formation of BRCA1-PALB2-BRCA2 complex. PALB2 (Partner and localizer of BRCA2) can function synergistically with a BRCA2 chimera (termed piccolo, or piBRCA2) to further promote strand invasion. These breaks can be caused by natural and medical radiation or other environmental exposures, but also occur when chromosomes exchange genetic material during a special type of cell division that creates sperm and eggs (meiosis). Double strand breaks are also generated during repair of DNA cross links. By repairing DNA, these proteins play a role in maintaining the stability of the human genome and prevent dangerous gene rearrangements that can lead to hematologic and other cancers.
Like BRCA1, BRCA2 probably regulates the activity of other genes and plays a critical role in embryo development.
Certain variations of the BRCA2 gene increase risks for breast cancer as part of a hereditary breast-ovarian cancer syndrome. Researchers have identified hundreds of mutations in the BRCA2 gene, many of which cause an increased risk of cancer. BRCA2 mutations are usually insertions or deletions of a small number of DNA base pairs in the gene. As a result of these mutations, the protein product of the BRCA2 gene is abnormal and does not function properly. Researchers believe that the defective BRCA2 protein is unable to help fix mutations that occur in other genes. As a result, mutations build up and can cause cells to divide in an uncontrolled way and form a tumor.
People who have two mutated copies of the BRCA2 gene have one type of Fanconi anemia. This condition is caused by extremely reduced levels of the BRCA2 protein in cells, which allows the accumulation of damaged DNA. Patients with Fanconi anemia are prone to several types of leukemia (a type of blood cell cancer); solid tumors, particularly of the head, neck, skin, and reproductive organs; and bone marrow suppression (reduced blood cell production that leads to anemia). Women having inherited a defective BRCA1 or BRCA2 gene have risks for breast and ovarian cancer that are so high and seem so selective that many mutation carriers choose to have prophylactic surgery. There has been much conjecture to explain such apparently striking tissue specificity. Major determinants of where BRCA1 and BRCA2 associated hereditary cancers occur are related to tissue specificity of the cancer pathogen, the agent that causes chronic inflammation or the carcinogen. The target tissue may have receptors for the pathogen, become selectively exposed to carcinogens and an infectious process. An innate genomic deficit impairs normal responses and exacerbates the susceptibility to disease in organ targets. This theory also fits data for several tumor suppressors beyond BRCA1 or BRCA2. A major advantage of this model is that it suggests there are some options in addition to prophylactic surgery.
In addition to breast cancer in men and women, mutations in BRCA2 also lead to an increased risk of ovarian, Fallopian tube, prostate, and pancreatic cancers, as well as malignant melanoma. In some studies, mutations in the central part of the gene have been associated with a higher risk of ovarian cancer and a lower risk of prostate cancer than mutations in other parts of the gene. Several other types of cancer have also been seen in certain families with BRCA2 mutations.
In general, strongly inherited gene mutations (including mutations in BRCA2) account for only 5-10% of breast cancer cases; the specific risk of getting breast or other cancer for anyone carrying a BRCA2 mutation depends on many factors.
|The BRCA2 gene was discovered in 1994 by Professor Michael Stratton and Dr Richard Wooster (Institute of Cancer Research, UK). The Wellcome Trust Sanger Institute (Hinxton, Cambs, UK) collaborated with Stratton and Wooster to isolate the gene.
In honour of this discovery and collaboration, the Wellcome Trust participated in the construction of a cycle and foot path between the Addenbrooke's Hospital site in Cambridge and the nearby village of Great Shelford in 2005. The path by Cambridgeshire County Council and Sustrans is decorated with 10,257 stripes of 4 colours representing the nucleotide sequence of BRCA2 (green representing adenine, blue representing cytosine, yellow representing guanine, and red representing thymine). It makes up part of National Cycle Route 11, and can be seen from trains running between Cambridge and London.
Germ line BRCA2 mutations and founder effect
All germ line BRCA2 mutations identified to date have been inherited, suggesting the possibility of a large “founder” effect in which a certain mutation is common to a well-defined population group and can theoretically be traced back to a common ancestor. Given the complexity of mutation screening for BRCA2, these common mutations may simplify the methods required for mutation screening in certain populations. Analysis of mutations that occur with high frequency also permits the study of their clinical expression. A striking example of a founder mutation is found in Iceland, where a single BRCA2 (999del5) mutation accounts for virtually all breast/ovarian cancer families. This frame-shift mutation leads to a highly truncated protein product. In a large study examining hundreds of cancer and control individuals, this 999del5 mutation was found in 0.6% of the general population. Of note, while 72% of patients who were found to be carriers had a moderate or strong family history of breast cancer, 28% had little or no family history of the disease. This strongly suggests the presence of modifying genes that affect the phenotypic expression of this mutation, or possibly the interaction of the BRCA2 mutation with environmental factors. Additional examples of founder mutations in BRCA2 are given in the table below.
|Population or subgroup||BRCA2 mutation(s)||Reference(s)|
|Finns||8555T>G, 999del5, IVS23-2A>G|||
|French Canadians||8765delAG, 3398delAAAAG|||
BRCA2 has been shown to interact with
- CREB-binding protein,
- SHFM1 and
BRCA2 contains a number of 39 amino acid repeats that are critical for binding to RAD51 (a key protein in DNA recombinational repair) and resistance to methyl methanesulphonate treatment.
The BRCA2 helical domain adopts a helical structure, consisting of a four-helix cluster core (alpha 1, alpha 8, alpha 9, alpha 10) and two successive beta-hairpins (beta 1 to beta 4). An approximately 50-amino acid segment that contains four short helices (alpha 2 to alpha 4), meanders around the surface of the core structure. In BRCA2, the alpha 9 and alpha 10 helices pack with the BRCA2 OB1 domain through van der Waals contacts involving hydrophobic and aromatic residues, and also through side-chain and backbone hydrogen bonds. This domain binds the 70-amino acid DSS1 (deleted in split-hand/split foot syndrome) protein, which was originally identified as one of three genes that map to a 1.5-Mb locus deleted in an inherited developmental malformation syndrome.
The BRCA OB1 domain assumes an OB fold, which consists of a highly curved five-stranded beta-sheet that closes on itself to form a beta-barrel. OB1 has a shallow groove formed by one face of the curved sheet and is demarcated by two loops, one between beta 1 and beta 2 and another between beta 4 and beta 5, which allows for weak single strand DNA binding. The domain also binds the 70-amino acid DSS1 (deleted in split-hand/split foot syndrome) protein.
The BRCA OB3 domain assumes an OB fold, which consists of a highly curved five-stranded beta-sheet that closes on itself to form a beta-barrel. OB3 has a pronounced groove formed by one face of the curved sheet and is demarcated by two loops, one between beta 1 and beta 2 and another between beta 4 and beta 5, which allows for strong ssDNA binding.
The Tower domain adopts a secondary structure consisting of a pair of long, antiparallel alpha-helices (the stem) that support a three-helix bundle (3HB) at their end. The 3HB contains a helix-turn-helix motif and is similar to the DNA binding domains of the bacterial site-specific recombinases, and of eukaryotic Myb and homeodomain transcription factors. The Tower domain has an important role in the tumour suppressor function of BRCA2, and is essential for appropriate binding of BRCA2 to DNA.
Patents, enforcement, litigation, and controversy
A patent application for the isolated BRCA1 gene and cancer-cancer promoting mutations, as well as methods to diagnose the likelihood of getting breast cancer, was filed by the University of Utah, National Institute of Environmental Health Sciences (NIEHS) and Myriad Genetics in 1994; over the next year, Myriad, in collaboration with other investigators, isolated and sequenced the BRCA2 gene and identified relevant mutations, and the first BRCA2 patent was filed in the U.S. by Myriad and the other institutions in 1995. Myriad is the exclusive licensee of these patents and has enforced them in the US against clinical diagnostic labs. This business model led from Myriad being a startup in 1994 to being a publicly traded company with 1200 employees and about $500M in annual revenue in 2012; it also led to controversy over high prices and the inability to get second opinions from other diagnostic labs, which in turn led to the landmark Association for Molecular Pathology v. Myriad Genetics lawsuit. The patents begin to expire in 2014.
According to an article published in the journal, Genetic Medicine, in 2010, "The patent story outside the United States is more complicated.... For example, patents have been obtained but the patents are being ignored by provincial health systems in Canada. In Australia and the UK, Myriad’s licensee permitted use by health systems, but announced a change of plans in August 2008. ... Only a single mutation has been patented in Myriad’s lone European-wide patent, although some patents remain under review of an opposition proceeding. In effect, the United States is the only jurisdiction where Myriad’s strong patent position has conferred sole-provide status." Peter Meldrum, CEO of Myriad Genetics, has acknowledged that Myriad has "other competitive advantages that may make such [patent] enforcement unnecessary" in Europe.
Legal decisions surrounding the BRCA1 and BRCA2 patents will affect the field of genetic testing in general. In June 2013, in Association for Molecular Pathology v. Myriad Genetics (No. 12-398), the US Supreme Court unanimously ruled that, "A naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated," invalidating Myriad's patents on the BRCA1 and BRCA2 genes. However, the Court also held that manipulation of a gene to create something not found in nature could still be eligible for patent protection. The Federal Court of Australia came to the opposite conclusion, upholding the validity of an Australian Myriad Genetics patent over the BRCA1 gene in February 2013, but this decision is being appealed and the appeal will include consideration of the US Supreme Court ruling.
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- Hejna J, Holtorf Megan, Hines Jennie, Mathewson Lauren, Hemphill Aaron, Al-Dhalimy Muhsen, Olson Susan B, Moses Robb E (April 2008). "Tip60 is required for DNA interstrand cross-link repair in the Fanconi anemia pathway". J. Biol. Chem. 283 (15): 9844–51. doi:10.1074/jbc.M709076200. PMC 2398728. PMID 18263878.
- Hussain S, Witt Emily, Huber Pia A J, Medhurst Annette L, Ashworth Alan, Mathew Christopher G (October 2003). "Direct interaction of the Fanconi anaemia protein FANCG with BRCA2/FANCD1". Hum. Mol. Genet. 12 (19): 2503–10. doi:10.1093/hmg/ddg266. PMID 12915460.
- Yuan Y, Shen Z (December 2001). "Interaction with BRCA2 suggests a role for filamin-1 (hsFLNa) in DNA damage response". J. Biol. Chem. 276 (51): 48318–24. doi:10.1074/jbc.M102557200. PMID 11602572.
- Marmorstein LY, Kinev A V, Chan G K, Bochar D A, Beniya H, Epstein J A, Yen T J, Shiekhattar R (January 2001). "A human BRCA2 complex containing a structural DNA binding component influences cell cycle progression". Cell 104 (2): 247–57. doi:10.1016/S0092-8674(01)00209-4. PMID 11207365.
- Hakimi M-A, Bochar Daniel A, Chenoweth Josh, Lane William S, Mandel Gail, Shiekhattar Ramin (May 2002). "A core-BRAF35 complex containing histone deacetylase mediates repression of neuronal-specific genes". Proc. Natl. Acad. Sci. U.S.A. 99 (11): 7420–5. doi:10.1073/pnas.112008599. PMC 124246. PMID 12032298.
- Marmorstein LY, Ouchi T, Aaronson S A (November 1998). "The BRCA2 gene product functionally interacts with p53 and RAD51". Proc. Natl. Acad. Sci. U.S.A. 95 (23): 13869–74. doi:10.1073/pnas.95.23.13869. PMC 24938. PMID 9811893.
- "Entrez Gene: PALB2 partner and localizer of BRCA2".
- Lin H-R, Ting Nicholas S Y, Qin Jun, Lee Wen-Hwa (September 2003). "M phase-specific phosphorylation of BRCA2 by Polo-like kinase 1 correlates with the dissociation of the BRCA2-P/CAF complex". J. Biol. Chem. 278 (38): 35979–87. doi:10.1074/jbc.M210659200. PMID 12815053.
- Fuks F, Milner J, Kouzarides T (November 1998). "BRCA2 associates with acetyltransferase activity when bound to P/CAF". Oncogene 17 (19): 2531–4. doi:10.1038/sj.onc.1202475. PMID 9824164.
- Lee MY, Daniels Matthew J, Venkitaraman Ashok R (January 2004). "Phosphorylation of BRCA2 by the Polo-like kinase Plk1 is regulated by DNA damage and mitotic progression". Oncogene 23 (4): 865–72. doi:10.1038/sj.onc.1207223. PMID 14647413.
- Sharan SK, Morimatsu M, Albrecht U, Lim D S, Regel E, Dinh C, Sands A, Eichele G, Hasty P, Bradley A (April 1997). "Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2". Nature 386 (6627): 804–10. doi:10.1038/386804a0. PMID 9126738.
- Yu DS, Sonoda Eiichiro, Takeda Shunichi, Huang Christopher L H, Pellegrini Luca, Blundell Tom L, Venkitaraman Ashok R (October 2003). "Dynamic control of Rad51 recombinase by self-association and interaction with BRCA2". Mol. Cell 12 (4): 1029–41. doi:10.1016/S1097-2765(03)00394-0. PMID 14580352.
- Chen PL, Chen C F, Chen Y, Xiao J, Sharp Z D, Lee W H (April 1998). "The BRC repeats in BRCA2 are critical for RAD51 binding and resistance to methyl methanesulfonate treatment". Proc. Natl. Acad. Sci. U.S.A. 95 (9): 5287–92. doi:10.1073/pnas.95.9.5287. PMC 20253. PMID 9560268.
- Wong AK, Pero R, Ormonde P A, Tavtigian S V, Bartel P L (December 1997). "RAD51 interacts with the evolutionarily conserved BRC motifs in the human breast cancer susceptibility gene brca2". J. Biol. Chem. 272 (51): 31941–4. doi:10.1074/jbc.272.51.31941. PMID 9405383.
- Katagiri T, Saito H, Shinohara A, Ogawa H, Kamada N, Nakamura Y, Miki Y (March 1998). "Multiple possible sites of BRCA2 interacting with DNA repair protein RAD51". Genes Chromosomes Cancer 21 (3): 217–22. doi:10.1002/(SICI)1098-2264(199803)21:3<217::AID-GCC5>3.0.CO;2-2. PMID 9523196.
- Pellegrini L, Yu David S, Lo Thomas, Anand Shubha, Lee MiYoung, Blundell Tom L, Venkitaraman Ashok R (November 2002). "Insights into DNA recombination from the structure of a RAD51-BRCA2 complex". Nature 420 (6913): 287–93. doi:10.1038/nature01230. PMID 12442171.
- Tarsounas M, Davies Adelina A, West Stephen C (January 2004). "RAD51 localization and activation following DNA damage". Philos. Trans. R. Soc. Lond., B, Biol. Sci. 359 (1441): 87–93. doi:10.1098/rstb.2003.1368. PMC 1693300. PMID 15065660.
- Wong JMS, Ionescu Daniela, Ingles C James (January 2003). "Interaction between BRCA2 and replication protein A is compromised by a cancer-predisposing mutation in BRCA2". Oncogene 22 (1): 28–33. doi:10.1038/sj.onc.1206071. PMID 12527904.
- Marston NJ, Richards W J, Hughes D, Bertwistle D, Marshall C J, Ashworth A (July 1999). "Interaction between the product of the breast cancer susceptibility gene BRCA2 and DSS1, a protein functionally conserved from yeast to mammals". Mol. Cell. Biol. 19 (7): 4633–42. PMC 84261. PMID 10373512.
- Yang H, Jeffrey Philip D, Miller Julie, Kinnucan Elspeth, Sun Yutong, Thoma Nicolas H, Zheng Ning, Chen Phang-Lang, Lee Wen-Hwa, Pavletich Nikola P (September 2002). "BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure". Science 297 (5588): 1837–48. doi:10.1126/science.297.5588.1837. PMID 12228710.
- Preobrazhenska O, Yakymovych Mariya, Kanamoto Takashi, Yakymovych Ihor, Stoika Rostyslav, Heldin Carl-Henrik, Souchelnytskyi Serhiy (August 2002). "BRCA2 and Smad3 synergize in regulation of gene transcription". Oncogene 21 (36): 5660–4. doi:10.1038/sj.onc.1205732. PMID 12165866.
- Bork P, Blomberg N, Nilges M (May 1996). "Internal repeats in the BRCA2 protein sequence". Nat. Genet. 13 (1): 22â€“3. doi:10.1038/ng0596-22. PMID 8673099.
- "ACLU sues over patents on breast cancer genes". CNN. Archived from the original on 15 May 2009. Retrieved 2009-05-14.
- Robert Cook-Deegan, MD et al (2010) Impact of Gene Patents and Licensing Practices on Access to Genetic Testing for Inherited Susceptibility to Cancer: Comparing Breast and Ovarian Cancers to Colon Cancers: Patents and Licensing for Breast, Ovarian and Colon Cancer Testing Genet Med.12(4 Suppl): S15–S38.
- Benowitz S (January 2003). "European groups oppose Myriad's latest patent on BRCA1". J. Natl. Cancer Inst. 95 (1): 8–9. doi:10.1093/jnci/95.1.8. PMID 12509391.
- Conley J, Vorhous D, Cook-Deegan J (2011-03-01). "How Will Myriad Respond to the Next Generation of BRCA Testing?". Robinson, Bradshaw, and Hinson. Retrieved 2012-12-09.
- "Genetics and Patenting". Human Genome Project Information. U.S. Department of Energy Genome Programs. 2010-07-07.
- Liptak, Adam (13 June 2013). "Supreme Court Rules Human Genes May Not Be Patented". New York Times. Retrieved 13 June 2013.
- Corderoy, Amy (February 15, 2013). "Landmark patent ruling over breast cancer gene BRCA1". Sydney Morning Herald. Retrieved June 14, 2013.
- Corderoy, Amy (June 14, 2013). "Companies can't patent genes, US court rules". Sydney Morning Herald. Retrieved June 14, 2013.
- Zou JP, Hirose Y, Siddique H, Rao VN, Reddy ES (1999). "Structure and expression of variant BRCA2a lacking the transactivation domain". Oncology Reports 6 (2): 437–40. PMID 10023017.
- Venkitaraman AR (2001). "Chromosome stability, DNA recombination and the BRCA2 tumour suppressor". Current Opinion in Cell Biology 13 (3): 338–43. doi:10.1016/S0955-0674(00)00217-9. PMID 11343905.
- Orelli BJ, Bishop DK (2001). "BRCA2 and homologous recombination". Breast Cancer Research 3 (5): 294–8. doi:10.1186/bcr310. PMC 138691. PMID 11597317.
- Daniel DC (2002). "Highlight: BRCA1 and BRCA2 proteins in breast cancer". Microscopy Research and Technique 59 (1): 68–83. doi:10.1002/jemt.10178. PMID 12242698.
- Tutt A, Ashworth A (2003). "The relationship between the roles of BRCA genes in DNA repair and cancer predisposition". Trends in Molecular Medicine 8 (12): 571–6. doi:10.1016/S1471-4914(02)02434-6. PMID 12470990.
- Gonçalves A, Viens P, Sobol H, et al. (2005). "[Molecular alterations in breast cancer: clinical implications and new analytical tools]". Revue de Médecine Interne 26 (6): 470–8. doi:10.1016/j.revmed.2004.11.012. PMID 15936476.
- Hay T, Clarke AR (2005). "DNA damage hypersensitivity in cells lacking BRCA2: a review of in vitro and in vivo data". Biochemical Society Transactions 33 (Pt 4): 715–7. doi:10.1042/BST0330715. PMID 16042582.
- Domchek SM, Weber BL (2006). "Clinical management of BRCA1 and BRCA2 mutation carriers". Oncogene 25 (43): 5825–31. doi:10.1038/sj.onc.1209881. PMID 16998496.
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- BRCA2 Protein at the US National Library of Medicine Medical Subject Headings (MeSH)
- GeneReviews/NCBI/NIH/UW entry on BRCA1 and BRCA2 Hereditary Breast/Ovarian Cancer
- OMIM entries on BRCA1 and BRCA2 Hereditary Breast/Ovarian Cancer
- EntrezGene 675
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- UCSC Genome Browser View
- Dunnen, Johan T. den; Antonarakis, Stylianos E. (2000). "Mutation nomenclature extensions and suggestions to describe complex mutations: A discussion". Human Mutation 15 (1): 7–12. doi:10.1002/(SICI)1098-1004(200001)15:1<7::AID-HUMU4>3.0.CO;2-N. PMID 10612815.
- UCSC Gene details page
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.
BRCA2, oligonucleotide/oligosaccharide-binding, domain 1 Provide feedback
Members of this family assume an OB fold, which consists of a highly curved five-stranded beta-sheet that closes on itself to form a beta-barrel. OB1 has a shallow groove formed by one face of the curved sheet and is demarcated by two loops, one between beta 1 and beta 2 and another between beta 4 and beta 5, which allows for weak single strand DNA binding. The domain also binds the 70-amino acid DSS1 (deleted in split-hand/split foot syndrome) protein, which was originally identified as one of three genes that map to a 1.5-Mb locus deleted in an inherited developmental malformation syndrome .
Yang H, Jeffrey PD, Miller J, Kinnucan E, Sun Y, Thoma NH, Zheng N, Chen PL, Lee WH, Pavletich NP; , Science 2002;297:1837-1848.: BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure. PUBMED:12228710 EPMC:12228710
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR015187
This domain assumes an OB fold, which consists of a highly curved five-stranded beta-sheet that closes on itself to form a beta-barrel. OB1 has a shallow groove formed by one face of the curved sheet and is demarcated by two loops, one between beta 1 and beta 2 and another between beta 4 and beta 5, which allows for weak single strand DNA binding. The domain also binds the 70-amino acid DSS1 (deleted in split-hand/split foot syndrome) protein, which was originally identified as one of three genes that map to a 1.5-Mb locus deleted in an inherited developmental malformation syndrome [PUBMED:12228710].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Biological process||double-strand break repair via homologous recombination (GO:0000724)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
- the number of sequences which exhibit this architecture
a textual description of the architecture, e.g. Gla, EGF x 2, Trypsin.
This example describes an architecture with one
Gladomain, followed by two consecutive
EGFdomains, and finally a single
- a link to the page in the Pfam site showing information about the sequence that the graphic describes
- the UniProt description of the protein sequence
- the number of residues in the sequence
- the Pfam graphic itself.
Note that you can see the family page for a particular domain by clicking on the graphic. You can also choose to see all sequences which have a given architecture by clicking on the Show link in each row.
Finally, because some families can be found in a very large number of architectures, we load only the first fifty architectures by default. If you want to see more architectures, click the button at the bottom of the page to load the next set.
Loading domain graphics...
We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics sequence database. More...
There are various ways to view or download the sequence alignments that we store. We provide several sequence viewers and a plain-text Stockholm-format file for download.
We make a range of alignments for each Pfam-A family:
- the curated alignment from which the HMM for the family is built
- the alignment generated by searching the sequence database using the HMM
- Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
- alignment generated by searching the NCBI sequence database using the family HMM
- alignment generated by searching the metagenomics sequence database using the family HMM
You can see the alignments as HTML or in three different sequence viewers:
- a Java applet developed at the University of Dundee. You will need Java installed before running jalview
- an HTML page showing the whole alignment.Please note: full Pfam alignments can be very large. These HTML views are extremely large and often cause problems for browsers. Please use either jalview or the Pfam viewer if you have trouble viewing the HTML version
- an HTML-based representation of the alignment, coloured according to the posterior-probability (PP) values from the HMM. As for the standard HTML view, heatmap alignments can also be very large and slow to render.
- Pfam viewer
- an HTML-based viewer that uses DAS to retrieve alignment fragments on request
You can download (or view in your browser) a text representation of a Pfam alignment in various formats:
You can also change the order in which sequences are listed in the alignment, change how insertions are represented, alter the characters that are used to represent gaps in sequences and, finally, choose whether to download the alignment or to view it in your browser directly.
You may find that large alignments cause problems for the viewers and the reformatting tool, so we also provide all alignments in Stockholm format. You can download either the plain text alignment, or a gzipped version of it.
We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
Format an alignment
We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.
HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...
If you find these logos useful in your own work, please consider citing the following article:
This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
Note: You can also download the data file for the tree.
Curation and family details
This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.
|Number in seed:||19|
|Number in full:||188|
|Average length of the domain:||125.00 aa|
|Average identity of full alignment:||36 %|
|Average coverage of the sequence by the domain:||6.93 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||5|
|Download:||download the raw HMM for this family|
Weight segments by...
Change the size of the sunburst
selected sequences to HMM
a FASTA-format file
- 0 sequences
- 0 species
This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
Colouring and labels
Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
Anomalies in the taxonomy tree
There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
Missing taxonomic levels
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.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
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.
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.
There are 2 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
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 BRCA-2_OB1 domain has been found. There are 3 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 seqence.
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