P33991 (MCM4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
DNA replication licensing factor MCM4
EC=3.6.4.12

Alternative name(s):
CDC21 homolog
P1-CDC21

Gene names

Name:	MCM4
Synonyms:	CDC21

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	863 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Acts as component of the MCM2-7 complex (MCM complex) which is the putative replicative helicase essential for 'once per cell cycle' DNA replication initiation and elongation in eukaryotic cells. The active ATPase sites in the MCM2-7 ring are formed through the interaction surfaces of two neighboring subunits such that a critical structure of a conserved arginine finger motif is provided in trans relative to the ATP-binding site of the Walker A box of the adjacent subunit. The six ATPase active sites, however, are likely to contribute differentially to the complex helicase activity. Ref.7
Catalytic activity	ATP + H2O = ADP + phosphate.
Subunit structure	Component of the MCM2-7 complex. The complex forms a toroidal hexameric ring with the proposed subunit order MCM2-MCM6-MCM4-MCM7-MCM3-MCM5 (By simililarity). Interacts with MCMBP. Ref.7 Ref.9 Ref.10
Subcellular location	Nucleus By similarity.
Involvement in disease	Natural killer cell and glucocorticoid deficiency with DNA repair defect (NKGCD) [MIM:609981]: An autosomal recessive disorder characterized by severe intra- and extrauterine growth retardation, microcephaly, decreased numbers of natural killer cells, and recurrent viral infections, most often affecting the respiratory tract and leading to respiratory failure. Affected individuals also have adrenal insufficiency requiring corticosteroid replacement therapy and may have an increased susceptibility to cancer. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.18 Ref.19 Ref.20
Miscellaneous	Early fractionation of eukaryotic MCM proteins yielded a variety of dimeric, trimeric and tetrameric complexes with unclear biological significance. Specifically a MCM467 subcomplex is shown to have in vitro helicase activity which is inhibited by the MCM2 subunit. The MCM2-7 hexamer is the proposed physiological active complex.
Sequence similarities	Belongs to the MCM family. Contains 1 MCM domain.

Ontologies

Keywords
Biological process	Cell cycle DNA replication
Cellular component	Nucleus
Coding sequence diversity	Polymorphism
Ligand	ATP-binding DNA-binding Nucleotide-binding
Molecular function	Helicase Hydrolase
PTM	Acetylation Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	DNA replication initiation Inferred from electronic annotation. Source: InterPro DNA strand elongation involved in DNA replication Traceable author statement. Source: Reactome DNA unwinding involved in replication Inferred from electronic annotation. Source: Compara G1/S transition of mitotic cell cycle Traceable author statement. Source: Reactome M/G1 transition of mitotic cell cycle Traceable author statement. Source: Reactome S phase of mitotic cell cycle Traceable author statement. Source: Reactome cell cycle checkpoint Traceable author statement. Source: Reactome
Cellular_component	MCM complex Inferred from direct assay Ref.10. Source: UniProtKB nucleoplasm Traceable author statement. Source: Reactome
Molecular_function	ATP binding Non-traceable author statement. Source: UniProtKB DNA helicase activity Inferred from electronic annotation. Source: Compara single-stranded DNA binding Inferred from electronic annotation. Source: Compara
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
MCM7	P33993	6	EBI-374938,EBI-355924
ORF	Q9Q2G4	3	EBI-374938,EBI-6248094	From a different organism.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Initiator methionine	1	1	Removed Ref.15
	Chain	2 – 863	862	DNA replication licensing factor MCM4		PRO_0000194101
Regions
	Domain	458 – 667	210	MCM
	Nucleotide binding	510 – 517	8	ATP Potential
	Motif	642 – 645	4	Arginine finger
Amino acid modifications
	Modified residue	2	1	N-acetylserine Ref.15 Ref.17
	Modified residue	26	1	Phosphoserine Ref.12
	Modified residue	31	1	Phosphoserine Ref.12
	Modified residue	32	1	Phosphoserine Ref.12 Ref.15
	Modified residue	34	1	Phosphoserine Ref.12
	Modified residue	120	1	Phosphoserine Ref.8 Ref.11 Ref.15 Ref.17
	Modified residue	131	1	Phosphoserine Ref.13 Ref.15 Ref.17
	Modified residue	142	1	Phosphoserine Ref.15
	Modified residue	145	1	Phosphoserine Ref.15
	Modified residue	220	1	N6-acetyllysine Ref.14
	Modified residue	450	1	N6-acetyllysine Ref.14
Natural variations
	Natural variant	460	1	E → G. Ref.2 Corresponds to variant rs17287663 [ dbSNP | Ensembl ].		VAR_020500
	Natural variant	650	1	L → M. Ref.1 Ref.3 Ref.6 Corresponds to variant rs762679 [ dbSNP | Ensembl ].		VAR_020501
Experimental info
	Sequence conflict	62	1	P → T in CAA52801. Ref.1
	Sequence conflict	206	1	P → Q in CAA52801. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	P33991 [UniParc]. Last modified May 10, 2005. Version 5. Checksum: 96D9CA2A7D88D015	FASTA	863	96,558
	10 20 30 40 50 60 MSSPASTPSR RGSRRGRATP AQTPRSEDAR SSPSQRRRGE DSTSTGELQP MPTSPGVDLQ 70 80 90 100 110 120 SPAAQDVLFS SPPQMHSSAI PLDFDVSSPL TYGTPSSRVE GTPRSGVRGT PVRQRPDLGS 130 140 150 160 170 180 AQKGLQVDLQ SDGAAAEDIV ASEQSLGQKL VIWGTDVNVA ACKENFQRFL QRFIDPLAKE 190 200 210 220 230 240 EENVGIDITE PLYMQRLGEI NVIGEPFLNV NCEHIKSFDK NLYRQLISYP QEVIPTFDMA 250 260 270 280 290 300 VNEIFFDRYP DSILEHQIQV RPFNALKTKN MRNLNPEDID QLITISGMVI RTSQLIPEMQ 310 320 330 340 350 360 EAFFQCQVCA HTTRVEMDRG RIAEPSVCGR CHTTHSMALI HNRSLFSDKQ MIKLQESPED 370 380 390 400 410 420 MPAGQTPHTV ILFAHNDLVD KVQPGDRVNV TGIYRAVPIR VNPRVSNVKS VYKTHIDVIH 430 440 450 460 470 480 YRKTDAKRLH GLDEEAEQKL FSEKRVELLK ELSRKPDIYE RLASALAPSI YEHEDIKKGI 490 500 510 520 530 540 LLQLFGGTRK DFSHTGRGKF RAEINILLCG DPGTSKSQLL QYVYNLVPRG QYTSGKGSSA 550 560 570 580 590 600 VGLTAYVMKD PETRQLVLQT GALVLSDNGI CCIDEFDKMN ESTRSVLHEV MEQQTLSIAK 610 620 630 640 650 660 AGIICQLNAR TSVLAAANPI ESQWNPKKTT IENIQLPHTL LSRFDLIFLL LDPQDEAYDR 670 680 690 700 710 720 RLAHHLVALY YQSEEQAEEE LLDMAVLKDY IAYAHSTIMP RLSEEASQAL IEAYVDMRKI 730 740 750 760 770 780 GSSRGMVSAY PRQLESLIRL AEAHAKVRLS NKVEAIDVEE AKRLHREALK QSATDPRTGI 790 800 810 820 830 840 VDISILTTGM SATSRKRKEE LAEALKKLIL SKGKTPALKY QQLFEDIRGQ SDIAITKDMF 850 860 EEALRALADD DFLTVTGKTV RLL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"A human homologue of the yeast replication protein Cdc21. Interactions with other Mcm proteins." Musahl C., Schulte D., Burkhart R., Knippers R. Eur. J. Biochem. 230:1096-1101(1995) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT MET-650.
[2]	NIEHS SNPs program Submitted (APR-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT GLY-460.
[3]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT MET-650. Tissue: Testis.
[4]	"The promoters for human DNA-PKcs (PRKDC) and MCM4: divergently transcribed genes located at chromosome 8 band q11." Connelly M.A., Zhang H., Kieleczawa J., Anderson C.W. Genomics 47:71-83(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-712.
[5]	"MCM4 and PRKDC, human genes encoding proteins MCM4 and DNA-PKcs, are close neighbours located on chromosome 8q12-->q13." Ladenburger E.M., Fackelmayer F.O., Hameister H., Knippers R. Cytogenet. Cell Genet. 77:268-270(1997) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] OF 1-23.
[6]	"The P1 family: a new class of nuclear mammalian proteins related to the yeast Mcm replication proteins." Hu B., Burkhart R., Schulte D., Musahl C., Knippers R. Nucleic Acids Res. 21:5289-5293(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 440-863, VARIANT MET-650. Tissue: Cervix.
[7]	"A DNA helicase activity is associated with an MCM4, -6, and -7 protein complex." Ishimi Y. J. Biol. Chem. 272:24508-24513(1997) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION IN THE MCM2-7 COMPLEX, FUNCTION.
[8]	"Global, in vivo, and site-specific phosphorylation dynamics in signaling networks." Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M. Cell 127:635-648(2006) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-120, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[9]	"Essential role of phosphorylation of MCM2 by Cdc7/Dbf4 in the initiation of DNA replication in mammalian cells." Tsuji T., Ficarro S.B., Jiang W. Mol. Biol. Cell 17:4459-4472(2006) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION IN THE MCM2-7 COMPLEX, ATPASE ACTIVITY OF THE MCM2-7 COMPLEX.
[10]	"Identification and characterization of a novel component of the human minichromosome maintenance complex." Sakwe A.M., Nguyen T., Athanasopoulos V., Shire K., Frappier L. Mol. Cell. Biol. 27:3044-3055(2007) [PubMed] [Europe PMC] [Abstract] Cited for: MASS SPECTROMETRY, HELICASE ACTIVITY OF THE MCM2-3 COMPLEX, INTERACTION WITH MCMBP, IDENTIFICATION IN THE MCM2-7 COMPLEX.
[11]	"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle." Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M. Mol. Cell 31:438-448(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-120, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[12]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-26; SER-31; SER-32 AND SER-34, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[13]	"Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions." Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K. Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-131, MASS SPECTROMETRY. Tissue: Leukemic T-cell.
[14]	"Lysine acetylation targets protein complexes and co-regulates major cellular functions." Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., Olsen J.V., Mann M. Science 325:834-840(2009) [PubMed] [Europe PMC] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-220 AND LYS-450, MASS SPECTROMETRY.
[15]	"Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis." Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M. Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-32; SER-120; SER-131; SER-142 AND SER-145, MASS SPECTROMETRY, CLEAVAGE OF INITIATOR METHIONINE. Tissue: Cervix carcinoma.
[16]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[17]	"System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation." Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B. Sci. Signal. 4:RS3-RS3(2011) [PubMed] [Europe PMC] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-120 AND SER-131, MASS SPECTROMETRY.
[18]	"MCM4 mutation causes adrenal failure, short stature, and natural killer cell deficiency in humans." Hughes C.R., Guasti L., Meimaridou E., Chuang C.H., Schimenti J.C., King P.J., Costigan C., Clark A.J., Metherell L.A. J. Clin. Invest. 122:814-820(2012) [PubMed] [Europe PMC] [Abstract] Cited for: INVOLVEMENT IN NKGCD.
[19]	"Partial MCM4 deficiency in patients with growth retardation, adrenal insufficiency, and natural killer cell deficiency." Gineau L., Cognet C., Kara N., Lach F.P., Dunne J., Veturi U., Picard C., Trouillet C., Eidenschenk C., Aoufouchi S., Alcais A., Smith O., Geissmann F., Feighery C., Abel L., Smogorzewska A., Stillman B., Vivier E., Casanova J.L., Jouanguy E. J. Clin. Invest. 122:821-832(2012) [PubMed] [Europe PMC] [Abstract] Cited for: INVOLVEMENT IN NKGCD.
[20]	"Recessive mutations in MCM4/PRKDC cause a novel syndrome involving a primary immunodeficiency and a disorder of DNA repair." Casey J.P., Nobbs M., McGettigan P., Lynch S., Ennis S. J. Med. Genet. 49:242-245(2012) [PubMed] [Europe PMC] [Abstract] Cited for: INVOLVEMENT IN NKGCD.
+	Additional computationally mapped references.

Web resources

NIEHS-SNPs

Cross-references

Sequence databases
EMBL GenBank DDBJ	X74794 mRNA. Translation: CAA52801.1. AY588245 Genomic DNA. Translation: AAS83108.1. BC031061 mRNA. Translation: AAH31061.1. U63630 Genomic DNA. Translation: AAC52018.1. U90415 Genomic DNA. Translation: AAB51723.3.
IPI	IPI00018349.
PIR	S65954.
RefSeq	NP_005905.2. NM_005914.3. NP_877423.1. NM_182746.2.
UniGene	Hs.460184.
3D structure databases
ProteinModelPortal	P33991.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP-31729N.
IntAct	P33991. 37 interactions.
MINT	MINT-1202120.
STRING	9606.ENSP00000262105.
PTM databases
PhosphoSite	P33991.
Polymorphism databases
DMDM	68571766.
Proteomic databases
PaxDb	P33991.
PeptideAtlas	P33991.
PRIDE	P33991.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000262105; ENSP00000262105; ENSG00000104738. ENST00000523944; ENSP00000430194; ENSG00000104738.
GeneID	4173.
KEGG	hsa:4173.
UCSC	uc003xqk.2. human.
Organism-specific databases
CTD	4173.
GeneCards	GC08P048873.
H-InvDB	HIX0007492.
HGNC	HGNC:6947. MCM4.
HPA	CAB004497. HPA004873.
MIM	602638. gene. 609981. phenotype.
neXtProt	NX_P33991.
Orphanet	75391. Immunodeficiency with natural-killer cell deficiency.
PharmGKB	PA30694.
GenAtlas	Search...
Phylogenomic databases
eggNOG	COG1241.
HOGENOM	HOG000224127.
HOVERGEN	HBG102781.
InParanoid	P33991.
KO	K02212.
OMA	VEMDRGR.
OrthoDB	EOG43XV2T.
PhylomeDB	P33991.
Enzyme and pathway databases
Reactome	REACT_115566. Cell Cycle. REACT_21300. Mitotic M-M/G1 phases. REACT_383. DNA Replication.
Gene expression databases
ArrayExpress	P33991.
Bgee	P33991.
CleanEx	HS_MCM4.
Genevestigator	P33991.
GermOnline	ENSG00000104738. Homo sapiens.
Family and domain databases
Gene3D	2.20.28.10. 1 hit. 2.40.50.140. 2 hits.
InterPro	IPR003593. AAA+_ATPase. IPR008047. MCM_4. IPR018525. MCM_CS. IPR001208. MCM_DNA-dep_ATPase. IPR012340. NA-bd_OB-fold. IPR004039. Rubredoxin-type_fold. [Graphical view]
Pfam	PF00493. MCM. 1 hit. [Graphical view]
PRINTS	PR01657. MCMFAMILY. PR01660. MCMPROTEIN4.
SMART	SM00382. AAA. 1 hit. SM00350. MCM. 1 hit. [Graphical view]
SUPFAM	SSF50249. Nucleic_acid_OB. 1 hit.
PROSITE	PS00847. MCM_1. 1 hit. PS50051. MCM_2. 1 hit. [Graphical view]
ProtoNet	Search...
Other
ChiTaRS	MCM4. human.
GenomeRNAi	4173.
NextBio	16436.
PMAP-CutDB	P33991.
SOURCE	Search...

Entry information

Entry name

MCM4_HUMAN

Accession

Primary (citable) accession number: P33991
Secondary accession number(s): Q8NEH1, Q99658

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 1, 1994
Last sequence update:	May 10, 2005
Last modified:	May 1, 2013
This is version 138 of the entry and version 5 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.