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Reviewed, UniProtKB/Swiss-Prot Q07820 (MCL1_HUMAN)

Last modified November 25, 2008. Version 89. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (7) | Third-party data | Customize display text xml rdf/xml gff fasta
Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Alternative products · Sequence annotation (Features) · Sequences · References · Cross-references · Entry information · Relevant documents

Names and origin

Protein namesRecommended name:
    Induced myeloid leukemia cell differentiation protein Mcl-1
Alternative name(s):
    Bcl-2-related protein EAT/mcl1
    mcl1/EAT
Gene names
Name: MCL1
OrganismHomo sapiens (Human)
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length350 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is not processed.
Protein existenceEvidence at protein level.

General annotation (Comments)

Function

Involved in the regulation of apoptosis versus cell survival, and in the maintenance of viability but not of proliferation. Mediates its effects by interactions with a number of other regulators of apoptosis. Isoform 1 inhibits apoptosis while isoform 2 promotes it.

Subunit structure

Interacts with BAD, BOK, BIK and BFM By similarity. Interacts with PMAIP1. Isoform 1 interacts with BAX, BAK1, TPT1 and BCL2L11. Heterodimer of isoform 1 and isoform 2. Homodimers of isoform 1 or isoform 2 are not detected. Isoform 2 does not interact with pro-apoptototic BCL2-related proteins.

Subcellular location

Membrane; Single-pass membrane proteinPotential. Cytoplasm. Mitochondrion. Nucleusnucleoplasm. Note= Cytoplasmic, associated with mitochondria.

Induction

Expression increases early during phorbol-ester induced differentiation along the monocyte/macrophage pathway in myeloid leukemia cell lines ML-1. Rapidly up-regulated by CSF2 in ML-1 cells. Up-regulated by heat-shock induced differentiation. Expression increases early during retinoic acid-induced differentiation.

Post-translational modification

Cleaved by CASP3 during apoptosis. In intact cells cleavage occurs preferentially after Asp-127, yielding a pro-apoptotic 28 kDa C-terminal fragment.

Rapidly degraded in the absence of phosphorylation on Thr-163 in the PEST region.

Phosphorylated on Thr-163. Treatment with taxol or okadaic acid induces phosphorylation on additional sites.

Sequence similarities

Belongs to the Bcl-2 family.

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: Q07820-1)

Also known as: MCL1L;

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 2 (identifier: Q07820-2)

Also known as: Delta S; MCL-1S; TM;

The sequence of this isoform differs from the canonical sequence as follows:
     231-271: MLRKLDIKNE...GRIVTLISFG → WVCGVLPCRG...FGISNKIALL
     272-350: Missing.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 350350Induced myeloid leukemia cell differentiation protein Mcl-1
PRO_0000143080

Regions

Transmembrane328 – 34821 Potential
Region104 – 17572PEST-like
Motif209 – 22315BH3
Motif252 – 27221BH1
Motif304 – 31916BH2

Sites

Site127 – 1282Cleavage; by caspase-3
Site157 – 1582Cleavage; by caspase-3

Amino acid modifications

Modified residue1211Phosphoserine
Modified residue1631Phosphothreonine; by MAPK
Cross-link5Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)
Cross-link40Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)
Cross-link136Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)
Cross-link194Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)
Cross-link197Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)

Natural variations

Alternative sequence231 – 27141MLRKL…LISFG → WVCGVLPCRGPRRWHQECAA GFCRCCWSRSWFGISNKIAL L in isoform 2.
VSP_000532
Alternative sequence272 – 35079Missing in isoform 2.
VSP_000533
Natural variant1731E → D: dbSNP rs2737820.
VAR_024021
Natural variant2271A → V: dbSNP rs11580946.
VAR_024022

Experimental info

Mutagenesis51K → R: Reduced ubiquitination
Mutagenesis401K → R: Reduced ubiquitination
Mutagenesis1271D → A: Abolishes formation of 28 and 17 kDa cleavage products by CASP3. Abolishes cleavage by caspase-3; when associated with A-157
Mutagenesis1361K → R: Reduced ubiquitination
Mutagenesis1571D → A: Abolishes formation of 23 and 21 kDa cleavage products by CASP3. Abolishes cleavage by caspase-3; when associated with A-127
Mutagenesis1621S → A: No effect
Mutagenesis1631T → A: Abolishes phosphorylation by MAPK. No effect on phosphorylation induced by okadaic acid or taxol
Mutagenesis1941K → R: Reduced ubiquitination
Mutagenesis1971K → R: Reduced ubiquitination
Mutagenesis2081K → R: No effect on ubiquitination
Mutagenesis2341K → R: No effect on ubiquitination

Secondary structure

.................. 350
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 (MCL1L) [UniParc].

Last modified December 6, 2005. Version 3.
Checksum: D85821AC59275F1F

FASTA35037,337
        10         20         30         40         50         60 
MFGLKRNAVI GLNLYCGGAG LGAGSGGATR PGGRLLATEK EASARREIGG GEAGAVIGGS 

        70         80         90        100        110        120 
AGASPPSTLT PDSRRVARPP PIGAEVPDVT ATPARLLFFA PTRRAAPLEE MEAPAADAIM 

       130        140        150        160        170        180 
SPEEELDGYE PEPLGKRPAV LPLLELVGES GNNTSTDGSL PSTPPPAEEE EDELYRQSLE 

       190        200        210        220        230        240 
IISRYLREQA TGAKDTKPMG RSGATSRKAL ETLRRVGDGV QRNHETAFQG MLRKLDIKNE 

       250        260        270        280        290        300 
DDVKSLSRVM IHVFSDGVTN WGRIVTLISF GAFVAKHLKT INQESCIEPL AESITDVLVR 

       310        320        330        340        350 
TKRDWLVKQR GWDGFVEFFH VEDLEGGIRN VLLAFAGVAG VGAGLAYLIR 

« Hide

Isoform 2 (Delta S) (MCL-1S) (TM) [UniParc].

Checksum: FAE0BF9E126523EF
Show »

27128,662

References

« Hide 'large scale' references
[1]"MCL1, a gene expressed in programmed myeloid cell differentiation, has sequence similarity to BCL2."
Kozopas K.M., Yang T., Buchan H.L., Zhou P., Craig R.W.
Proc. Natl. Acad. Sci. U.S.A. 90:3516-3520(1993) [PubMed: 7682708] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT ASP-173.
Tissue: Myeloid leukemia cell.
[2]"Induction of mcl1/EAT, Bcl-2 related gene, by retinoic acid or heat shock in the human embryonal carcinoma cells, NCR-G3."
Umezawa A., Maruyama T., Inazawa J., Imai S., Takano T., Hata J.
Cell Struct. Funct. 21:143-150(1996) [PubMed: 8790944] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), INDUCTION.
[3]"Functional analysis of the human MCL-1 gene."
Akgul C., Turner P.C., White M.R.H., Edwards S.W.
Cell. Mol. Life Sci. 57:684-691(2000) [PubMed: 11130466] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[4]"Exon skipping in Mcl-1 results in a Bcl-2 homology domain 3 only gene product that promotes cell death."
Bingle C.D., Craig R.W., Swales B.M., Singleton V., Zhou P., Whyte M.K.B.
J. Biol. Chem. 275:22136-22146(2000) [PubMed: 10766760] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS 1 AND 2), VARIANT ASP-173, FUNCTION.
Tissue: Myeloid leukemia cell and Neuroblastoma.
[5]"MCL-1S, a splicing variant of the antiapoptotic BCL-2 family member MCL-1, encodes a proapoptotic protein possessing only the BH3 domain."
Bae J., Leo C.P., Hsu S.Y., Hsueh A.J.W.
J. Biol. Chem. 275:25255-25261(2000) [PubMed: 10837489] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), INTERACTION WITH BAX; BAK1; BCL2L11 AND BETWEEN ISOFORMS 1 AND 2.
[6]"Cloning of human full-length CDSs in BD Creator(TM) system donor vector."
Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A.
Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
[7]"NIEHS-SNPs, environmental genome project, NIEHS ES15478, Department of Genome Sciences, Seattle, WA (URL: http://egp.gs.washington.edu)."
Livingston R.J., Rieder M.J., Shaffer T., Bertucci C., Baier C.N., Rajkumar N., Willa H.T., Daniels M., Downing T.K., Stanaway I.B., Nguyen C.P., Gildersleeve H., Cassidy C.M., Johnson E.J., Swanson J.E., McFarland I., Yool B., Park C., Nickerson D.A.
Submitted (JUN-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT VAL-227.
[8]"The DNA sequence and biological annotation of human chromosome 1."
Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K. expand/collapse author list , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.
Nature 441:315-321(2006) [PubMed: 16710414] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[9]"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: 15489334] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
Tissue: Mammary gland and Placenta.
[10]"Acute myeloid leukemia possessing jumping translocation is related to highly elevated levels of EAT/mcl-1, a Bcl-2 related gene with anti-apoptotic functions."
Okita H., Umezawa A., Fukuma M., Hata J.
Leuk. Res. 24:73-77(2000) [PubMed: 10634649] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 182-289 (ISOFORM 1), VARIANT VAL-227.
Tissue: Ewing sarcoma.
[11]"Mcl-1 is required for Akata6 B-lymphoma cell survival and is converted to a cell death molecule by efficient caspase-mediated cleavage."
Michels J., O'Neill J.W., Dallman C.L., Mouzakiti A., Habens F., Brimmell M., Zhang K.Y.J., Craig R.W., Marcusson E.G., Johnson P.W.M., Packham G.
Oncogene 23:4818-4827(2004) [PubMed: 15122313] [Abstract]
Cited for: PROTEIN SEQUENCE OF N-TERMINUS OF FRAGMENTS OBTAINED BY CASPASE CLEAVAGE, MUTAGENESIS OF ASP-127 AND ASP-157.
[12]"Mcl-1 is an immediate-early gene activated by the granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling pathway and is one component of the GM-CSF viability response."
Chao J.-R., Wang J.-M., Lee S.-F., Peng H.-W., Lin Y.-H., Chou C.-H., Li J.-C., Huang H.-M., Chou C.-K., Kuo M.-L., Yen J.J.-Y., Yang-Yen H.-F.
Mol. Cell. Biol. 18:4883-4898(1998) [PubMed: 9671497] [Abstract]
Cited for: INDUCTION.
[13]"Physical and functional interaction between myeloid cell leukemia 1 protein (MCL1) and fortilin. The potential role of MCL1 as a fortilin chaperone."
Zhang D., Li F., Weidner D., Mnjoyan Z.H., Fujise K.
J. Biol. Chem. 277:37430-37438(2002) [PubMed: 12149273] [Abstract]
Cited for: INTERACTION WITH TPT1, SUBCELLULAR LOCATION.
[14]"Phosphorylation and inactivation of myeloid cell leukemia 1 by JNK in response to oxidative stress."
Inoshita S., Takeda K., Hatai T., Terada Y., Sano M., Hata J., Umezawa A., Ichijo H.
J. Biol. Chem. 277:43730-43734(2002) [PubMed: 12223490] [Abstract]
Cited for: PHOSPHORYLATION AT SER-121 AND THR-163.
[15]"Mitochondrial p53 activates Bak and causes disruption of a Bak-Mcl1 complex."
Leu J.I.-J., Dumont P., Hafey M., Murphy M.E., George D.L.
Nat. Cell Biol. 6:443-450(2004) [PubMed: 15077116] [Abstract]
Cited for: INTERACTION WITH BAK, SUBCELLULAR LOCATION.
[16]"MCL1 is phosphorylated in the PEST region and stabilized upon ERK activation in viable cells, and at additional sites with cytotoxic okadaic acid or taxol."
Domina A.M., Vrana J.A., Gregory M.A., Hann S.R., Craig R.W.
Oncogene 23:5301-5315(2004) [PubMed: 15241487] [Abstract]
Cited for: PHOSPHORYLATION AT THR-163, MUTAGENESIS OF SER-162 AND THR-163.
[17]"Mule/ARF-BP1, a BH3-only E3 ubiquitin ligase, catalyzes the polyubiquitination of Mcl-1 and regulates apoptosis."
Zhong Q., Gao W., Du F., Wang X.
Cell 121:1085-1095(2005) [PubMed: 15989957] [Abstract]
Cited for: UBIQUITINATION, MUTAGENESIS OF LYS-5; LYS-40; LYS-136; LYS-194; LYS-197; LYS-208 AND LYS-234.
[18]"Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient phosphoproteomic analysis."
Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D., Yates J.R. III
J. Proteome Res. 7:1346-1351(2008) [PubMed: 18220336] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-163, MASS SPECTROMETRY.
[19]"Structural insights into the degradation of Mcl-1 induced by BH3 domains."
Czabotar P.E., Lee E.F., van Delft M.F., Day C.L., Smith B.J., Huang D.C.S., Fairlie W.D., Hinds M.G., Colman P.M.
Proc. Natl. Acad. Sci. U.S.A. 104:6217-6222(2007) [PubMed: 17389404] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (1.55 ANGSTROMS) OF 151-307 IN COMPLEXES WITH PMAIP1 AND BCL2L11.
[20]"X-ray crystal structure of human MCL-1 in complex with BIM BH3."
Bare E., Grant R.A., Keating A.E.
Submitted (JUN-2007) to the PDB data bank
Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 172-327 IN COMPLEX WITH BCL2L11.
+Additional computationally mapped references.