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105  structures 1512  species 0  interactions 9514  sequences 249  architectures

Family: MCM (PF00493)

Summary: MCM P-loop 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 P-loop domain Provide feedback

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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.

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 six 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).

The presence of a putative ATP-binding domain implies that these proteins may be involved in an ATP-consuming step in the initiation of DNA replication in eukaryotes.

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan P-loop_NTPase (CL0023), which has the following description:

AAA family proteins often perform chaperone-like functions that assist in the assembly, operation, or disassembly of protein complexes [2].

The clan contains the following 229 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 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 DUF1611 DUF1726 DUF2075 DUF2326 DUF2478 DUF257 DUF2791 DUF2813 DUF3584 DUF463 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 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 MutS_V Myosin_head NACHT NB-ARC NOG1 NTPase_1 NTPase_P4 ORC3_N 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 RHSP RNA12 RNA_helicase Roc RsgA_GTPase RuvB_N SbcCD_C SecA_DEAD Septin Sigma54_activ_2 Sigma54_activat SKI SMC_N SNF2_N Spore_IV_A SRP54 SRPRB SulA Sulfotransfer_1 Sulfotransfer_2 Sulfotransfer_3 Sulfotransfer_4 Sulphotransf SWI2_SNF2 T2SSE T4SS-DNA_transf Terminase_1 Terminase_3 Terminase_6 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 Zeta_toxin Zot

Alignments

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  Seed
(58)
Full
(9514)
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(18121)
NCBI
(65509)
Meta
(1789)
RP15
(2860)
RP35
(5341)
RP55
(7521)
RP75
(9191)
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  Seed
(58)
Full
(9514)
Representative proteomes UniProt
(18121)
NCBI
(65509)
Meta
(1789)
RP15
(2860)
RP35
(5341)
RP55
(7521)
RP75
(9191)
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  Seed
(58)
Full
(9514)
Representative proteomes UniProt
(18121)
NCBI
(65509)
Meta
(1789)
RP15
(2860)
RP35
(5341)
RP55
(7521)
RP75
(9191)
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

Seed source: Prosite
Previous IDs: none
Type: Domain
Sequence Ontology: SO:0000417
Author: Bateman A , Finn RD
Number in seed: 58
Number in full: 9514
Average length of the domain: 203.10 aa
Average identity of full alignment: 48 %
Average coverage of the sequence by the domain: 26.61 %

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 23.3 23.3
Trusted cut-off 23.3 23.3
Noise cut-off 23.2 23.2
Model length: 224
Family (HMM) version: 23
Download: download the raw HMM for this family

Species distribution

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Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
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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 domain has been found. There are 105 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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