Summary: MCM P-loop domain
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Minichromosome maintenance Edit Wikipedia article
Overall Structure of the Mcm2-7 double hexamer
|Pfam maps to the core ATP binding domain.|
The minichromosome maintenance protein complex (MCM) is a DNA helicase essential for genomic DNA replication. Eukaryotic MCM consists of six gene products, Mcm2â€“7, which form a heterohexamer. As a critical protein for cell division, MCM is also the target of various checkpoint pathways, such as the S-phase entry and S-phase arrest checkpoints. Both the loading and activation of MCM helicase are strictly regulated and are coupled to cell growth cycles. Deregulation of MCM function has been linked to genomic instability and a variety of carcinomas.
- 1 History and structure
- 2 Function in DNA replication initiation and elongation
- 3 Role in replication licensing
- 4 Biochemical structure
- 5 Models of DNA unwinding
- 6 Role in cancer
- 7 See also
- 8 References
- 9 External links
History and structure
The minichromosome maintenance proteins were named after a yeast genetics screen for mutants defective in the regulation of DNA replication initiation. The rationale behind this screen was that if replication origins were regulated in a manner analogous to transcription promoters, where transcriptional regulators showed promoter specificity, then replication regulators should also show origin specificity. Since eukaryotic chromosomes contain multiple replication origins and the plasmids contain only one, a slight defect in these regulators would have a dramatic effect on the replication of plasmids but little effect on chromosomes. In this screen, mutants conditional for plasmid loss were identified. In a secondary screen, these conditional mutants were selected for defects in plasmid maintenance against a collection of plasmids each carrying a different origin sequence. Two classes of mcm mutants were identified: Those that affected the stability of all minichromosomes and others that affected the stability of only a subset of the minichromosomes. The former were mutants defective in chromosome segregation such as mcm16, mcm20 and mcm21. Among the latter class of origin-specific mutants were mcm1, mcm2, mcm3, mcm5 and mcm10. Later on, others identified Mcm4, Mcm6 and Mcm7 in yeasts and other eukaryotes based on homology to Mcm2p, Mcm3p and Mcm5p expanding the MCM family to six, subsequently known as the Mcm2-7 family. In archaea, the heterohexamer ring is replaced by a homohexamer made up of a single type mcm protein, pointing at a history of gene duplicaion and diversification.
Function in DNA replication initiation and elongation
MCM2-7 is required for both DNA replication initiation and elongation; its regulation at each stage is a central feature of eukaryotic DNA replication. During G1 phase, the two head-to-head Mcm2-7 rings serve as the scaffold for the assembly of the bidirectional replication initiation complexes at the replication origin. During S phase, the Mcm2-7 complex forms the catalytic core of the Cdc45-MCM-GINS helicase - the DNA unwinding engine of the replisome.
G1/pre-replicative complex assembly
Site selection for replication origins is carried out by the Origin Recognition Complex (ORC), a six subunit complex (Orc1-6). During the G1 phase of the cell cycle, Cdc6 is recruited by ORC to form a launching pad for the loading of two head-to-head Mcm2-7 hexamers, also known as the pre-replication complex (pre-RC). There is genetic and biochemical evidence that the recruitment of the double hexamer may involve either one or two ORCs. Soluble Mcm2-7 hexamer forms a flexible left-handed open-ringed structure stabilised by Cdt1 prior to its loading onto chromatin, one at a time. The structure of the ORC-Cdc6-Cdt1-MCM (OCCM) intermediate formed after the loading of the first Cdt1-Mcm2-7 heptamer indicates that the winged helix domain at the C-terminal extensions (CTE) of the Mcm2-7 complex firmly anchor onto the surfaces created by the ORC-Cdc6 ring structure around origin DNA. The fusion of the two head-to-head Mcm2-7 hexamers is believed to be facilitated by the removal of Cdt1, leaving the NTDs of the two MCM hexamers flexible for inter-ring interactions. The loading of MCM2-7 onto DNA is an active process that requires ATP hydrolysis by both Orc1-6 and Cdc6. This process is coined "Replication Licensing" as it is a prerequisite for DNA replication initiation in every cell division cycle.
Late G1/early S - initiation
In late G1/early S phase, the pre-RC is activated for DNA unwinding by the cyclin-dependent kinases (CDKs) and DDK. This facilitates the loading of additional replication factors (e.g., Cdc45, MCM10, GINS, and DNA polymerases) and unwinding of the DNA at the origin. Once pre-RC formation is complete, Orc1-6 and Cdc6 are no longer required for MCM2-7 retention at the origin, and they are dispensable for subsequent DNA replication.
Upon entry into S phase, the activity of the CDKs and the Dbf4-dependent kinase (DDK) Cdc7 promotes the assembly of replication forks, likely in part by activating MCM2-7 to unwind DNA. Following DNA polymerase loading, bidirectional DNA replication commences.
During S phase, Cdc6 and Cdt1 are degraded or inactivated to block additional pre-RC formation, and bidirectional DNA replication ensues. When the replication fork encounters lesions in the DNA, the S-phase checkpoint response slows or stops fork progression and stabilizes the association of MCM2-7 with the replication fork during DNA repair.
Role in replication licensing
The replication licensing system acts to ensure that the no section of the genome is replicated more than once in a single cell cycle.
The inactivation of any of at least five of the six MCM subunits during S phase quickly blocks ongoing elongation. As a critical mechanism to ensure only a single round of DNA replication, the loading of additional MCM2-7 complexes into pre-RCs is inactivated by redundant means after passage into S phase. 
MCM2-7 activity can also be regulated during elongation. The loss of replication fork integrity, an event precipitated by DNA damage, unusual DNA sequence, or insufficient deoxyribonucleotide precursors, can lead to the formation of DNA double-strand breaks and chromosome rearrangements. Normally, these replication problems trigger an S-phase checkpoint that minimizes genomic damage by blocking further elongation and physically stabilizing protein-DNA associations at the replication fork until the problem is fixed. This stabilization of the replication fork requires the physical interaction of MCM2-7 with Mrc1, Tof1, and Csm3 (M/T/C complex). In the absence of these proteins, dsDNA unwinding and replisome movement powered by MCM2-7 continue, but DNA synthesis stops. At least part of this stop is due to the dissociation of polymerase Îµ from the replication fork.
Each subunit in the MCM structure contains two large N- and C-terminal domains. The N-terminal domain consists of three small sub-domains and appears to be used mainly for structural organization. The N-domain can coordinate with a neighboring subunitâ€™s C-terminal AAA+ helicase domain through a long and conserved loop. This conserved loop, named the allosteric control loop, has been shown to play a role in regulating interactions between N- and C-terminal regions by facilitating communication between the domains in response to ATP hydrolysis . The N-domain also establishes the in vitro 3â€²â†’5â€² directionality of MCM. 
Models of DNA unwinding
Regarding the physical mechanism of how a hexameric helicase unwinds DNA, two models have been proposed based on in vivo and in vitro data. In the "steric" model, the helicase tightly translocates along one strand of DNA while physically displacing the complementary strand. In the "pump" model, pairs of hexameric helicases unwind duplex DNA by either twisting it apart or extruding it through channels in the complex.
The steric model hypothesizes that the helicase encircles dsDNA and, after local melting of the duplex DNA at the origin, translocates away from the origin, dragging a rigid proteinaceous "wedge" (either part of the helicase itself or another associated protein) that separates the DNA strands.
The pump model postulates that multiple helicases load at replication origins, translocate away from one another, and in some manner eventually become anchored in place. They then rotate dsDNA in opposite directions, resulting in the unwinding of the double helix in the intervening region. The pump model has also been proposed to be restricted to the melting of origin DNA while the Mcm2-7 complexes are still anchored at the origin just before replication initiation.
Role in cancer
Various MCMs have been shown to promote cell proliferation in vitro and in vivo especially in certain types of cancer cell lines. The association between MCMs and proliferation in cancer cell lines is mostly attributed to its ability to enhance DNA replication. The roles of MCM2 and MCM7 in cell proliferation have been demonstrated in various cellular contexts and even in human specimens. 
MCM2 has been shown to be frequently expressed in proliferating premalignant lung cells. Its expression was associated with cells having a higher proliferation potential in non-dysplastic squamous epithelium, malignant fibrous histiocytomas, and endometrial carcinoma, while MCM2 expression was also correlated higher mitotic index in breast cancer specimens. 
Similarly, many research studies have shown the link between MCM7 expression and cell proliferation. Expression of MCM7 was significantly correlated with the expression of Ki67 in choriocarcinomas, lung cancer, papillary urothelial neoplasia, esophageal cancer, and endometrial cancer. Its expression was also associated with a higher proliferative index in prostatic intraepithelial neoplasia and cancer.
- Li N, Zhai Y, Zhang Y, Li W, Yang M, Lei J, Tye BK, Gao N (August 2015). "Structure of the eukaryotic MCM complex at 3.8 Ã…". Nature. 524 (7564): 186â€“91. Bibcode:2015Natur.524..186L. doi:10.1038/nature14685. PMID 26222030.
- Zhai Y, Cheng E, Wu H, Li N, Yung PY, Gao N, Tye BK (March 2017). "Open-ringed structure of the Cdt1-Mcm2-7 complex as a precursor of the MCM double hexamer". Nature Structural & Molecular Biology. 24 (3): 300â€“308. doi:10.1038/nsmb.3374. PMID 28191894.
- Bochman ML, Schwacha A (December 2009). "The Mcm complex: unwinding the mechanism of a replicative helicase". Microbiology and Molecular Biology Reviews. 73 (4): 652â€“83. doi:10.1128/mmbr.00019-09. PMC 2786579. PMID 19946136.
- Shima N, Alcaraz A, Liachko I, Buske TR, Andrews CA, Munroe RJ, Hartford SA, Tye BK, Schimenti JC (January 2007). "A viable allele of Mcm4 causes chromosome instability and mammary adenocarcinomas in mice". Nature Genetics. 39 (1): 93â€“8. doi:10.1038/ng1936. PMID 17143284.
- Tye BK (June 1999). "MCM proteins in DNA replication". Annual Review of Biochemistry. 68 (1): 649â€“86. doi:10.1146/annurev.biochem.68.1.649. PMID 10872463.
- Maine GT, Sinha P, Tye BK (March 1984). "Mutants of S. cerevisiae defective in the maintenance of minichromosomes". Genetics. 106 (3): 365â€“85. PMC 1224244. PMID 6323245.
- Ausiannikava, Darya; Allers, Thorsten (31 January 2017). "Diversity of DNA Replication in the Archaea". Genes. 8 (2): 56. doi:10.3390/genes8020056. PMC 5333045. PMID 28146124.
- Passmore S, Elble R, Tye BK (July 1989). "A protein involved in minichromosome maintenance in yeast binds a transcriptional enhancer conserved in eukaryotes". Genes & Development. 3 (7): 921â€“35. doi:10.1101/gad.3.7.921. PMID 2673922.
- Chang VK, Fitch MJ, Donato JJ, Christensen TW, Merchant AM, Tye BK (February 2003). "Mcm1 binds replication origins". The Journal of Biological Chemistry. 278 (8): 6093â€“100. doi:10.1074/jbc.M209827200. PMID 12473677.
- Merchant AM, Kawasaki Y, Chen Y, Lei M, Tye BK (June 1997). "A lesion in the DNA replication initiation factor Mcm10 induces pausing of elongation forks through chromosomal replication origins in Saccharomyces cerevisiae". Molecular and Cellular Biology. 17 (6): 3261â€“71. doi:10.1128/MCB.17.6.3261. PMC 232179. PMID 9154825.
- Homesley L, Lei M, Kawasaki Y, Sawyer S, Christensen T, Tye BK (April 2000). "Mcm10 and the MCM2-7 complex interact to initiate DNA synthesis and to release replication factors from origins". Genes & Development. 14 (8): 913â€“26. doi:10.1101/gad.14.8.913 (inactive 2019-12-12). PMC 316538. PMID 10783164.
- Bell SP, Stillman B (May 1992). "ATP-dependent recognition of eukaryotic origins of DNA replication by a multiprotein complex". Nature. 357 (6374): 128â€“34. doi:10.1038/357128a0. PMID 1579162.
- Li N, Lam WH, Zhai Y, Cheng J, Cheng E, Zhao Y, Gao N, Tye BK (July 2018). "Structure of the origin recognition complex bound to DNA replication origin". Nature. 559 (7713): 217â€“222. doi:10.1038/s41586-018-0293-x. PMID 29973722.
- Diffley JF, Cocker JH, Dowell SJ, Harwood J, Rowley A (1995). "Stepwise assembly of initiation complexes at budding yeast replication origins during the cell cycle". Journal of Cell Science. Supplement. 19: 67â€“72. doi:10.1242/jcs.1995.supplement_19.9. PMID 8655649.
- Ticau S, Friedman LJ, Ivica NA, Gelles J, Bell SP (April 2015). "Single-molecule studies of origin licensing reveal mechanisms ensuring bidirectional helicase loading". Cell. 161 (3): 513â€“525. doi:10.1016/j.cell.2015.03.012. PMC 4445235. PMID 25892223.
- Coster G, Diffley JF (July 2017). "Bidirectional eukaryotic DNA replication is established by quasi-symmetrical helicase loading". Science. 357 (6348): 314â€“318. doi:10.1126/science.aan0063. PMC 5608077. PMID 28729513.
- Frigola J, He J, Kinkelin K, Pye VE, Renault L, Douglas ME, Remus D, Cherepanov P, Costa A, Diffley JF (June 2017). "Cdt1 stabilizes an open MCM ring for helicase loading". Nature Communications. 8: 15720. doi:10.1038/ncomms15720. PMC 5490006. PMID 28643783.
- Ticau S, Friedman LJ, Champasa K, CorrÃªa IR, Gelles J, Bell SP (March 2017). "Mechanism and timing of Mcm2-7 ring closure during DNA replication origin licensing". Nature Structural & Molecular Biology. 24 (3): 309â€“315. doi:10.1038/nsmb.3375. PMC 5336523. PMID 28191892.
- Yuan Z, Riera A, Bai L, Sun J, Nandi S, Spanos C, Chen ZA, Barbon M, Rappsilber J, Stillman B, Speck C, Li H (March 2017). "Structural basis of Mcm2-7 replicative helicase loading by ORC-Cdc6 and Cdt1". Nature Structural & Molecular Biology. 24 (3): 316â€“324. doi:10.1038/nsmb.3372. PMC 5503505. PMID 28191893.
- Zhai Y, Li N, Jiang H, Huang X, Gao N, Tye BK (July 2017). "Unique Roles of the Non-identical MCM Subunits in DNA Replication Licensing". Molecular Cell. 67 (2): 168â€“179. doi:10.1016/j.molcel.2017.06.016. PMID 28732205.
- Randell JC, Bowers JL, RodrÃguez HK, Bell SP (January 2006). "Sequential ATP hydrolysis by Cdc6 and ORC directs loading of the Mcm2-7 helicase". Molecular Cell. 21 (1): 29â€“39. doi:10.1016/j.molcel.2005.11.023. PMID 16387651.
- Tye BK (May 1994). "The MCM2-3-5 proteins: are they replication licensing factors?". Trends in Cell Biology. 4 (5): 160â€“6. doi:10.1016/0962-8924(94)90200-3. PMID 14731643.
- ThÃ¶mmes P, Kubota Y, Takisawa H, Blow JJ (June 1997). "The RLF-M component of the replication licensing system forms complexes containing all six MCM/P1 polypeptides". The EMBO Journal. 16 (11): 3312â€“9. doi:10.1093/emboj/16.11.3312. PMC 1169947. PMID 9214646.
- Kamimura Y, Tak YS, Sugino A, Araki H (April 2001). "Sld3, which interacts with Cdc45 (Sld4), functions for chromosomal DNA replication in Saccharomyces cerevisiae". The EMBO Journal. 20 (8): 2097â€“107. doi:10.1093/emboj/20.8.2097. PMC 125422. PMID 11296242.
- Tada S, Blow JJ (August 1998). "The replication licensing system". Biological Chemistry. 379 (8â€“9): 941â€“9. doi:10.1515/bchm.1998.379.8-9.941. PMC 3604913. PMID 9792427.
- Neves H, Kwok HF (August 2017). "In sickness and in health: The many roles of the minichromosome maintenance proteins". Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 1868 (1): 295â€“308. doi:10.1016/j.bbcan.2017.06.001. PMID 28579200.
- Katou Y, Kanoh Y, Bando M, Noguchi H, Tanaka H, Ashikari T, Sugimoto K, Shirahige K (August 2003). "S-phase checkpoint proteins Tof1 and Mrc1 form a stable replication-pausing complex". Nature. 424 (6952): 1078â€“83. Bibcode:2003Natur.424.1078K. doi:10.1038/nature01900. PMID 12944972.
- Liu W, Pucci B, Rossi M, Pisani FM, Ladenstein R (June 2008). "Structural analysis of the Sulfolobus solfataricus MCM protein N-terminal domain". Nucleic Acids Research. 36 (10): 3235â€“43. doi:10.1093/nar/gkn183. PMC 2425480. PMID 18417534.
- Brewster AS, Chen XS (June 2010). "Insights into the MCM functional mechanism: lessons learned from the archaeal MCM complex". Critical Reviews in Biochemistry and Molecular Biology. 45 (3): 243â€“56. doi:10.3109/10409238.2010.484836. PMC 2953368. PMID 20441442.
- Barry ER, McGeoch AT, Kelman Z, Bell SD (2007-02-01). "Archaeal MCM has separable processivity, substrate choice and helicase domains". Nucleic Acids Research. 35 (3): 988â€“98. doi:10.1093/nar/gkl1117. PMC 1807962. PMID 17259218.
- Georgescu, Roxana; Yuan, Zuanning; Bai, Lin; de Luna Almeida Santos, Ruda; Sun, Jingchuan; Zhang, Dan; Yurieva, Olga; Li, Huilin; Oâ€™Donnell, Michael E. (31 January 2017). "Structure of eukaryotic CMG helicase at a replication fork and implications to replisome architecture and origin initiation". Proceedings of the National Academy of Sciences. 114 (5): E697â€“E706. doi:10.1073/pnas.1620500114. PMC 5293012. PMID 28096349.
- Patel SS, Picha KM (2000-06-01). "Structure and function of hexameric helicases". Annual Review of Biochemistry. 69 (1): 651â€“97. doi:10.1146/annurev.biochem.69.1.651. PMID 10966472.
- Laskey RA, Madine MA (January 2003). "A rotary pumping model for helicase function of MCM proteins at a distance from replication forks". EMBO Reports. 4 (1): 26â€“30. doi:10.1038/sj.embor.embor706. PMC 1315806. PMID 12524516.
- Gonzalez MA, Pinder SE, Callagy G, Vowler SL, Morris LS, Bird K, Bell JA, Laskey RA, Coleman N (December 2003). "Minichromosome maintenance protein 2 is a strong independent prognostic marker in breast cancer". Journal of Clinical Oncology. 21 (23): 4306â€“13. doi:10.1200/jco.2003.04.121. PMID 14645419.
- Guan B, Wang X, Yang J, Zhou C, Meng Y (August 2015). "Minichromosome maintenance complex component 7 has an important role in the invasion of papillary urothelial neoplasia". Oncology Letters. 10 (2): 946â€“950. doi:10.3892/ol.2015.3333. PMC 4509410. PMID 26622601.
- Cortez D, Glick G, Elledge SJ (July 2004). "Minichromosome maintenance proteins are direct targets of the ATM and ATR checkpoint kinases". Proceedings of the National Academy of Sciences of the United States of America. 101 (27): 10078â€“83. doi:10.1073/pnas.0403410101. PMC 454167. PMID 15210935.
- Humphries C (2001-01-12). "Molecular Bureaucrat Tied to Replication Approval Process". Focus. Harvard Medical, Dental, and Public Health Schools. Archived from the original on 2007-08-31. Retrieved 2008-10-03.
- macromolecular structures of MCM at the EM Data Bank(EMDB)
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.
MCM P-loop domain Provide feedback
No Pfam abstract.
Koonin EV; , Nucleic Acids Res 1993;21:2541-2547.: A common set of conserved motifs in a vast variety of putative nucleic acid-dependent ATPases including MCM proteins involved in the initiation of eukaryotic DNA replication. PUBMED:8332451 EPMC:8332451
Internal database links
|SCOOP:||AAA AAA_14 AAA_16 AAA_18 AAA_2 AAA_22 AAA_3 AAA_30 AAA_32 AAA_33 AAA_5 AAA_7 bpMoxR IstB_IS21 Mg_chelatase RuvB_N Sigma54_activ_2 Sigma54_activat T2SSE TIP49|
|Similarity to PfamA using HHSearch:||AAA Sigma54_activat Mg_chelatase NTPase_1 RuvB_N TniB AAA_2 AAA_3 AAA_5 AAA_18 AAA_22 AAA_28|
This tab holds annotation information from the InterPro database.
InterPro entry IPR001208
Proteins shown to be required for the initiation of eukaryotic DNA replication share a highly conserved domain of about 210 amino-acid residues [ PUBMED:1454522 , PUBMED:8265339 , PUBMED:14731643 ]. The latter shows some similarities [ PUBMED:8332451 ] with that of various other families of DNA-dependent ATPases. Eukaryotes seem to possess a family of eight proteins that contain this domain. They were first identified in yeast where most of them have a direct role in the initiation of chromosomal DNA replication by interacting directly with autonomously replicating sequences (ARS). They were thus called 'minichromosome maintenance proteins' with gene symbols prefixed by MCM. These six proteins are:
- MCM2, also known as cdc19 (in S.pombe).
- MCM3, also known as DNA polymerase alpha holoenzyme-associated protein P1, RLF beta subunit or ROA.
- MCM4, also known as CDC54, cdc21 (in S.pombe) or dpa (in Drosophila).
- MCM5, also known as CDC46 or nda4 (in S.pombe).
- MCM6, also known as mis5 (in S.pombe).
- MCM7, also known as CDC47 or Prolifera (in A.thaliana).
- MCM8, also known as as REC (in Drosophila).
These proteins are evolutionarily related and belong to the AAA+ superfamily. They contain the Mcm family domain, which includes motifs that are required for ATP hydrolysis (such as the Walker A and B, and R-finger motifs). Mcm2-7 forms a hexameric complex which is the replicative helicase involved in replication initiation and elongation, whereas Mcm8 and Mcm9 from and separate one, conserved among many eukaryotes except yeast and C. elegans. Mcm8/9 complex play a role during replication elongation or recombination, being involved in the repair of double-stranded DNA breaks and DNA interstrand cross-links by homologous recombination. Drosophila is the only organism that has MCM8 without MCM9, involved in meiotic recombination [ PUBMED:22771115 , PUBMED:30743181 ].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||DNA binding (GO:0003677)|
|ATP binding (GO:0005524)|
|Biological process||DNA duplex unwinding (GO:0032508)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
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AAA family proteins often perform chaperone-like functions that assist in the assembly, operation, or disassembly of protein complexes .
The clan contains the following 243 members:6PF2K AAA AAA-ATPase_like AAA_10 AAA_11 AAA_12 AAA_13 AAA_14 AAA_15 AAA_16 AAA_17 AAA_18 AAA_19 AAA_2 AAA_21 AAA_22 AAA_23 AAA_24 AAA_25 AAA_26 AAA_27 AAA_28 AAA_29 AAA_3 AAA_30 AAA_31 AAA_32 AAA_33 AAA_34 AAA_35 AAA_5 AAA_6 AAA_7 AAA_8 AAA_9 AAA_PrkA ABC_ATPase ABC_tran ABC_tran_Xtn Adeno_IVa2 Adenylsucc_synt ADK AFG1_ATPase AIG1 APS_kinase Arf ArsA_ATPase ATP-synt_ab ATP_bind_1 ATP_bind_2 ATPase ATPase_2 Bac_DnaA BCA_ABC_TP_C Beta-Casp bpMoxR Cas_Csn2 Cas_St_Csn2 CbiA CBP_BcsQ CDC73_C CENP-M CFTR_R CLP1_P CMS1 CoaE CobA_CobO_BtuR CobU cobW CPT CSM2 CTP_synth_N Cytidylate_kin Cytidylate_kin2 DAP3 DBINO DEAD DEAD_2 DLIC DNA_pack_C DNA_pack_N DNA_pol3_delta DNA_pol3_delta2 DnaB_C dNK DO-GTPase1 DO-GTPase2 DUF1611 DUF1726 DUF2075 DUF2326 DUF2478 DUF257 DUF2791 DUF2813 DUF3584 DUF463 DUF5906 DUF6079 DUF815 DUF853 DUF87 DUF927 Dynamin_N Dynein_heavy Elong_Iki1 ELP6 ERCC3_RAD25_C Exonuc_V_gamma FeoB_N Fer4_NifH Flavi_DEAD FTHFS FtsK_SpoIIIE G-alpha Gal-3-0_sulfotr GBP GBP_C GTP_EFTU Gtr1_RagA Guanylate_kin GvpD HDA2-3 Helicase_C Helicase_C_2 Helicase_C_4 Helicase_RecD Herpes_Helicase Herpes_ori_bp Herpes_TK HSA HydF_dimer HydF_tetramer Hydin_ADK IIGP IPPT IPT iSTAND IstB_IS21 KAP_NTPase KdpD Kinase-PPPase Kinesin KTI12 LAP1C Lon_2 LpxK MCM MeaB MEDS Mg_chelatase Microtub_bd MipZ MMR_HSR1 MMR_HSR1_C MobB MukB Mur_ligase_M MutS_V Myosin_head NACHT NAT_N NB-ARC NOG1 NTPase_1 NTPase_P4 OPA1_C ORC3_N P-loop_TraG ParA Parvo_NS1 PAXNEB PduV-EutP PhoH PIF1 Ploopntkinase1 Ploopntkinase2 Ploopntkinase3 Podovirus_Gp16 Polyoma_lg_T_C Pox_A32 PPK2 PPV_E1_C PRK PSY3 Rad17 Rad51 Ras RecA ResIII RHD3 RhoGAP_pG1_pG2 RHSP RNA12 RNA_helicase Roc RsgA_GTPase RuvB_N SbcCD_C SecA_DEAD Septin Sigma54_activ_2 Sigma54_activat SKI SMC_N SNF2-rel_dom Spore_III_AA Spore_IV_A SRP54 SRPRB SulA Sulfotransfer_1 Sulfotransfer_2 Sulfotransfer_3 Sulfotransfer_4 Sulfotransfer_5 Sulphotransf SWI2_SNF2 T2SSE T4SS-DNA_transf Terminase_1 Terminase_3 Terminase_6N Terminase_GpA Thymidylate_kin TIP49 TK TniB Torsin TraG-D_C tRNA_lig_kinase TrwB_AAD_bind TsaE UvrB UvrD-helicase UvrD_C UvrD_C_2 Viral_helicase1 VirC1 VirE YqeC Zeta_toxin Zot
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 (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets and the UniProtKB 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 UniProtKB 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.
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.
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.
|Author:||Bateman A , Finn RD|
|Number in seed:||58|
|Number in full:||13501|
|Average length of the domain:||204.90 aa|
|Average identity of full alignment:||48 %|
|Average coverage of the sequence by the domain:||26.61 %|
|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:||25|
|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.
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 MCM domain has been found. There are 238 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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