Reviewed, UniProtKB/Swiss-Prot Q07820 (MCL1_HUMAN)

Names and origin

Protein names

Recommended name:
    Induced myeloid leukemia cell differentiation protein Mcl-1
Alternative name(s):
    Bcl-2-related protein EAT/mcl1
    mcl1/EAT

Gene names

Name:

MCL1

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	350 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence 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. Nucleus › nucleoplasm. 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.

Ontologies

Keywords
Biological process	Apoptosis Differentiation
Cellular component	Cytoplasm Membrane Mitochondrion Nucleus
Coding sequence diversity	Alternative splicing Polymorphism
Domain	Transmembrane
Molecular function	Developmental protein
PTM	Phosphoprotein Ubl conjugation
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Biological process	anti-apoptosis Ref.5 Traceable author statement. Source: UniProtKB apoptotic program Ref.1 Traceable author statement. Source: ProtInc cell fate determination Ref.5 Non-traceable author statement. Source: UniProtKB cellular homeostasis Ref.5 Non-traceable author statement. Source: UniProtKB multicellular organismal development Ref.2 Traceable author statement. Source: ProtInc
Cellular component	integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW mitochondrial outer membrane Ref.5 Traceable author statement. Source: UniProtKB nucleus Inferred from electronic annotation. Source: UniProtKB-KW
Molecular function	protein channel activity Ref.5 Traceable author statement. Source: UniProtKB protein heterodimerization activity Ref.5 Inferred from physical interaction. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
BAK1	Q16611	3	EBI-1003422,EBI-519866
BBC3	Q9BXH1	1	EBI-1003422,EBI-519884
BID	P55957	1	EBI-1003422,EBI-519672
BIK	Q13323	1	EBI-1003422,EBI-700794
bim-alpha1	Q8WYM1	1	EBI-1003422,EBI-1002160
Bmf	Q91ZE9	1	EBI-1003422,EBI-708032	From a different organism.
PMAIP1	Q13794	1	EBI-1003422,EBI-707392
Pmaip1	Q9JM54	1	EBI-1003422,EBI-709183	From a different organism.

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 key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 350

350

Induced myeloid leukemia cell differentiation protein Mcl-1

PRO_0000143080

Regions

Transmembrane

328 – 348

21

Potential

Region

104 – 175

72

PEST-like

Motif

209 – 223

15

BH3

Motif

252 – 272

21

BH1

Motif

304 – 319

16

BH2

Sites

Site

127 – 128

2

Cleavage; by caspase-3

Site

157 – 158

2

Cleavage; by caspase-3

Amino acid modifications

Modified residue

121

1

Phosphoserine

Modified residue

163

1

Phosphothreonine; by MAPK

Cross-link

5

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)

Cross-link

40

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)

Cross-link

136

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)

Cross-link

194

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)

Cross-link

197

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)

Natural variations

Alternative sequence

231 – 271

41

MLRKL…LISFG → WVCGVLPCRGPRRWHQECAA GFCRCCWSRSWFGISNKIAL L in isoform 2.

VSP_000532

Alternative sequence

272 – 350

79

Missing in isoform 2.

VSP_000533

Natural variant

173

1

E → D: dbSNP rs2737820.

VAR_024021

Natural variant

227

1

A → V: dbSNP rs11580946.

VAR_024022

Experimental info

Mutagenesis

5

1

K → R: Reduced ubiquitination

Mutagenesis

40

1

K → R: Reduced ubiquitination

Mutagenesis

127

1

D → A: Abolishes formation of 28 and 17 kDa cleavage products by CASP3. Abolishes cleavage by caspase-3; when associated with A-157

Mutagenesis

136

1

K → R: Reduced ubiquitination

Mutagenesis

157

1

D → A: Abolishes formation of 23 and 21 kDa cleavage products by CASP3. Abolishes cleavage by caspase-3; when associated with A-127

Mutagenesis

162

1

S → A: No effect

Mutagenesis

163

1

T → A: Abolishes phosphorylation by MAPK. No effect on phosphorylation induced by okadaic acid or taxol

Mutagenesis

194

1

K → R: Reduced ubiquitination

Mutagenesis

197

1

K → R: Reduced ubiquitination

Mutagenesis

208

1

K → R: No effect on ubiquitination

Mutagenesis

234

1

K → R: No effect on ubiquitination

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

350

Helix Strand Turn

Details...

Helix

173 – 191

19

Helix

204 – 221

18

Helix

225 – 235

11

Helix

244 – 253

10

Helix

254 – 256

3

Helix

261 – 281

21

Helix

288 – 301

14

Helix

303 – 308

6

Turn

309 – 311

3

Helix

312 – 318

7

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (MCL1L) [UniParc]. Last modified December 6, 2005. Version 3. Checksum: D85821AC59275F1F	FASTA	350	37,337
	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
	Isoform 2 (Delta S) (MCL-1S) (TM) [UniParc]. Checksum: FAE0BF9E126523EF		271	28,662
	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 WVCGVLPCRG 250 260 270 PRRWHQECAA GFCRCCWSRS WFGISNKIAL L

References

	« Hide 'large scale' referencesShow '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. , 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.