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103  structures 1478  species 0  interactions 8646  sequences 212  architectures

Family: MCM_lid (PF17855)

Summary: MCM AAA-lid domain

Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.

This is the Wikipedia entry entitled "Minichromosome maintenance". More...

Minichromosome maintenance Edit Wikipedia article

MCM2/3/5 family
PDB 1ltl EBI.jpg
Structure of MCM from archaeal M. Thermoautotrophicum.[1]
Identifiers
Symbol MCM
Pfam PF00493
Pfam clan CL0023
InterPro IPR001208
SMART SM00350
PROSITE PDOC00662

The minichromosome maintenance protein complex (MCM) is a DNA helicase essential for genomic DNA replication. Eukaryotic MCM consists of six gene products, MCM2–7, which form a heterohexamer.[2] 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.[3]

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.[3]

G1/initiation

During the G1 phase of the cell cycle, Cdc6 and Cdt1 recruit and load MCM2-7 to origins of replication (marked by the binding of Orc1-6) to form a stable and inactive complex called the pre-replication complex (pre-RC).[4]

All six MCM subunits colocalize to origins of replication during pre-RC formation. The inactivation or loss of any of the six MCM subunits during G1 phase blocks pre-RC formation in vivo in yeast and in vitro with Xenopus extracts.[5] The loading of MCM2-7 onto DNA is an active process that requires ATP hydrolysis by both Orc1-6 and Cdc6. 

Late G1/early S

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.[3] 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.

S-phase/elongation

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.[6]

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.[7]

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. [8]

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).[9] 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 ε from the replication fork.[9]

Biochemical structure

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.[10] The N-domain can coordinate with a neighboring subunit’s C-terminal AAA+ helicase domain through a long and conserved loop.[11] 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 [10]. The N-domain also establishes the in vitro 3′→5′ directionality of MCM. [12]

Models of DNA unwinding by MCM2-7

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.

Steric model

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.[13]

Pump model

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.[14]

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. [8]

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. [15]

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.[16]

See also

References

  1. ^ Fletcher RJ, Bishop BE, Leon RP, Sclafani RA, Ogata CM, Chen XS (March 2003). "The structure and function of MCM from archaeal M. Thermoautotrophicum". Nature Structural Biology. 10 (3): 160–7. doi:10.1038/nsb893. PMID 12548282. 
  2. ^ Carpentieri, Floriana; Felice, Mariarita De; Falco, Mariarosaria De; Rossi, Mosè; Pisani, Francesca M. (2002-04-05). "Physical and Functional Interaction between the Mini-chromosome Maintenance-like DNA Helicase and the Single-stranded DNA Binding Protein from the Crenarchaeon Sulfolobus solfataricus". Journal of Biological Chemistry. 277 (14): 12118–12127. doi:10.1074/jbc.m200091200. ISSN 0021-9258. PMID 11821426. 
  3. ^ a b c Bochman, Matthew L.; Schwacha, Anthony (2009-12-01). "The Mcm Complex: Unwinding the Mechanism of a Replicative Helicase". Microbiology and Molecular Biology Reviews. 73 (4): 652–683. doi:10.1128/mmbr.00019-09. ISSN 1092-2172. PMC 2786579Freely accessible. PMID 19946136. 
  4. ^ Tye, Bik K. (1999-06-01). "MCM Proteins in DNA Replication". Annual Review of Biochemistry. 68 (1): 649–686. doi:10.1146/annurev.biochem.68.1.649. ISSN 0066-4154. 
  5. ^ Masuda, Taro; Mimura, Satoru; Takisawa, Haruhiko (2003-02-01). "CDK- and Cdc45-dependent priming of the MCM complex on chromatin during S-phase in Xenopus egg extracts: possible activation of MCM helicase by association with Cdc45". Genes to Cells. 8 (2): 145–161. doi:10.1046/j.1365-2443.2003.00621.x. ISSN 1365-2443. 
  6. ^ Kamimura, Yoichiro; Tak, Yon-Soo; Sugino, Akio; Araki, Hiroyuki (2001-04-17). "Sld3, which interacts with Cdc45 (Sld4), functions for chromosomal DNA replication in Saccharomyces cerevisiae". The EMBO Journal. 20 (8): 2097–2107. doi:10.1093/emboj/20.8.2097. ISSN 0261-4189. PMC 125422Freely accessible. PMID 11296242. 
  7. ^ Tada, S.; Blow, J. J. (August 1998). "The replication licensing system". Biological Chemistry. 379 (8–9): 941–949. ISSN 1431-6730. PMC 3604913Freely accessible. PMID 9792427. 
  8. ^ a b Neves, Henrique; Kwok, Hang Fai (2017). "In sickness and in health: The many roles of the minichromosome maintenance proteins". Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 1868 (1): 295–308. doi:10.1016/j.bbcan.2017.06.001. 
  9. ^ a b Katou, Yuki; Kanoh, Yutaka; Bando, Masashige; Noguchi, Hideki; Tanaka, Hirokazu; Ashikari, Toshihiko; Sugimoto, Katsunori; Shirahige, Katsuhiko (August 2003). "S-phase checkpoint proteins Tof1 and Mrc1 form a stable replication-pausing complex". Nature. 424 (6952): 1078–1083. doi:10.1038/nature01900. ISSN 1476-4687. 
  10. ^ Liu, Wei; Pucci, Biagio; Rossi, Mosè; Pisani, Francesca M.; Ladenstein, Rudolf (2008-06-01). "Structural analysis of the Sulfolobus solfataricus MCM protein N-terminal domain". Nucleic Acids Research. 36 (10): 3235–3243. doi:10.1093/nar/gkn183. ISSN 0305-1048. 
  11. ^ Brewster, Aaron S.; Chen, Xiaojiang S. (2010-06-01). "Insights into the MCM functional mechanism: lessons learned from the archaeal MCM complex". Critical Reviews in Biochemistry and Molecular Biology. 45 (3): 243–256. doi:10.3109/10409238.2010.484836. ISSN 1040-9238. PMC 2953368Freely accessible. 
  12. ^ Barry, Elizabeth R.; McGeoch, Adam T.; Kelman, Zvi; Bell, Stephen D. (2007-02-01). "Archaeal MCM has separable processivity, substrate choice and helicase domains". Nucleic Acids Research. 35 (3): 988–998. doi:10.1093/nar/gkl1117. ISSN 0305-1048. 
  13. ^ Patel, S. S.; Picha, K. M. (2000-06-01). "Structure and Function of Hexameric Helicases". Annual Review of Biochemistry. 69 (1): 651–697. doi:10.1146/annurev.biochem.69.1.651. ISSN 0066-4154. 
  14. ^ Laskey, Ronald A.; Madine, Mark A. (2003-01-01). "A rotary pumping model for helicase function of MCM proteins at a distance from replication forks". EMBO Reports. 4 (1): 26–30. doi:10.1038/sj.embor.embor706. ISSN 1469-221X. PMC 1315806Freely accessible. PMID 12524516. 
  15. ^ Gonzalez, Michael A.; Pinder, Sarah E.; Callagy, Grace; Vowler, Sarah L.; Morris, Lesley S.; Bird, Kate; Bell, Jane A.; Laskey, Ronald A.; Coleman, Nicholas (2003-12-01). "Minichromosome Maintenance Protein 2 Is a Strong Independent Prognostic Marker in Breast Cancer". Journal of Clinical Oncology. 21 (23): 4306–4313. doi:10.1200/jco.2003.04.121. ISSN 0732-183X. 
  16. ^ 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): 946–950. doi:10.3892/ol.2015.3333. PMC 4509410Freely accessible. PMID 26622601. 
  17. ^ Cortez D, Glick G, Elledge SJ (July 2004). "Minichromosome maintenance proteins are direct targets of the ATM and ATR checkpoint kinases". Proc. Natl. Acad. Sci. U.S.A. 101 (27): 10078–83. doi:10.1073/pnas.0403410101. PMC 454167Freely accessible. PMID 15210935. 

External links

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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 AAA-lid domain Provide feedback

This entry represents the AAA-lid domain found in MCM proteins.

Literature references

  1. 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

This tab holds annotation information from the InterPro database.

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Domain organisation

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Pfam Clan

This family is a member of clan AAA_lid (CL0671), which has the following description:

Many AAA+ proteins have a C-terminal alpha-helical bundle in addition to the AAA core [1]. The functional roles of the helical bundle are varied and include the formation of a lid over the nucleotide binding site and mediation of subunit interactions in oligomeric protein complexes [1].

The clan contains the following 22 members:

AAA_assoc_2 AAA_lid_1 AAA_lid_10 AAA_lid_11 AAA_lid_2 AAA_lid_3 AAA_lid_4 AAA_lid_5 AAA_lid_6 AAA_lid_7 AAA_lid_8 AAA_lid_9 CbbQ_C ClpB_D2-small Dpoe2NT MCM_lid Mg_chelatase_C ORC4_C PCP_red TIP49_C UVR Vps4_C

Alignments

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  Seed
(58)
Full
(8646)
Representative proteomes UniProt
(13318)
NCBI
(15135)
Meta
(149)
RP15
(2529)
RP35
(4777)
RP55
(6780)
RP75
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  Seed
(58)
Full
(8646)
Representative proteomes UniProt
(13318)
NCBI
(15135)
Meta
(149)
RP15
(2529)
RP35
(4777)
RP55
(6780)
RP75
(8314)
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  Seed
(58)
Full
(8646)
Representative proteomes UniProt
(13318)
NCBI
(15135)
Meta
(149)
RP15
(2529)
RP35
(4777)
RP55
(6780)
RP75
(8314)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download   Download  
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Trees

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.

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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.

Curation View help on the curation process

This family is new in this Pfam release.

Seed source: ECOD
Previous IDs: none
Type: Domain
Sequence Ontology: SO:0000417
Author: Bateman A , Finn RD
Number in seed: 58
Number in full: 8646
Average length of the domain: 86.50 aa
Average identity of full alignment: 33 %
Average coverage of the sequence by the domain: 10.61 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 45638612 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 26.6 26.6
Trusted cut-off 26.6 26.6
Noise cut-off 26.5 26.5
Model length: 87
Family (HMM) version: 1
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Species distribution

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Archea Archea Eukaryota Eukaryota
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Viroids Viroids Unclassified sequence Unclassified sequence

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Structures

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_lid domain has been found. There are 103 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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