Reviewed, UniProtKB/Swiss-Prot Q07817 (BCLX_HUMAN)

Names and origin

Protein names

Recommended name:
    Apoptosis regulator Bcl-X
Alternative name(s):
    Bcl-2-like 1 protein

Gene names

Name:	BCL2L1
Synonyms:	BCL2L, BCLX

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	233 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Potent inhibitor of cell death. Isoform Bcl-X(L) anti-apoptotic activity is inhibited by association with SIVA isoform 1. Inhibits activation of caspases By similarity. Appears to regulate cell death by blocking the voltage-dependent anion channnel (VDAC) by binding to it and preventing the release of the caspase activator, cytochrome c, from the mitochondrial membrane. The Bcl-X(S) isoform promotes apoptosis.
Subunit structure	Bcl-X(L) forms homodimers, and heterodimers with BAX, BAK and BCL2. Heterodimerization with BAX does not seem to be required for anti-apoptotic activity. Also interacts with BAD and BBC3. Isoform Bcl-X(L) binds to Siva isoform 1. Interacts with BCL2L11 By similarity. Interacts with BECN1 and PGAM5.
Subcellular location	Mitochondrion membrane; Single-pass membrane proteinBy similarity. Nucleus membrane; Single-pass membrane protein; Cytoplasmic sideBy similarity. Note= Mitochondrial membranes and perinuclear envelope By similarity.
Tissue specificity	Bcl-X(S) is expressed at high levels in cells that undergo a high rate of turnover, such as developing lymphocytes. In contrast, Bcl-X(L) is found in tissues containing long-lived postmitotic cells, such as adult brain.
Domain	The BH4 motif is required for anti-apoptotic activity. The BH1 and BH2 motifs are required for both heterodimerization with other Bcl-2 family members and for repression of cell death.
Post-translational modification	Proteolytically cleaved by caspases during apoptosis. The cleaved protein, lacking the BH4 motif, has pro-apoptotic activity.
Sequence similarities	Belongs to the Bcl-2 family.

Ontologies

Keywords
Biological process	Apoptosis
Cellular component	Membrane Mitochondrion Nucleus
Coding sequence diversity	Alternative splicing
Domain	Transmembrane
Technical term	3D-structure
Gene Ontology (GO)
Biological process	negative regulation of survival gene product expression Ref.1 Traceable author statement. Source: ProtInc regulation of mitochondrial membrane permeability Inferred from direct assay. Source: HGNC regulation of mitochondrial membrane potential Inferred from direct assay. Source: HGNC release of cytochrome c from mitochondria Inferred from direct assay. Source: HGNC
Cellular component	integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW mitochondrial outer membrane Non-traceable author statement. Source: UniProtKB nuclear membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	identical protein binding Inferred from physical interaction. Source: IntAct
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
itself		3	EBI-287195,EBI-287195
BAD	Q92934	3	EBI-287195,EBI-700771
Bad	Q61337	1	EBI-78035,EBI-400328	From a different organism.
Bad	Q61337	2	EBI-287195,EBI-400328	From a different organism.
BAK1	Q16611	5	EBI-287195,EBI-519866
BAX	Q07812	1	EBI-78035,EBI-516580
BAX	Q07812	2	EBI-287195,EBI-516580
BBC3	Q9BXH1	1	EBI-78035,EBI-519884
BBC3	Q9BXH1	5	EBI-287195,EBI-519884
Bbc3	Q99ML1	2	EBI-287195,EBI-727801	From a different organism.
BCAP31	P51572	1	EBI-78035,EBI-77683
Bcl2l1	Q64373-1	1	EBI-287195,EBI-526380	From a different organism.
BCL2L11	O43521	4	EBI-287195,EBI-526406
BCL2L11	O43521-1	1	EBI-287195,EBI-526416
Bcl2l11	O54918	1	EBI-287195,EBI-526067	From a different organism.
BID	P55957	1	EBI-78035,EBI-519672
BID	P55957	1	EBI-287195,EBI-519672
BIK	Q13323	1	EBI-78035,EBI-700794
BIK	Q13323	2	EBI-287195,EBI-700794
bim-alpha1	Q8WYM1	1	EBI-78035,EBI-1002160
Bmf	Q91ZE9	1	EBI-78035,EBI-708032	From a different organism.
Bmf	Q91ZE9	1	EBI-287195,EBI-708032	From a different organism.
ced-4	P30429	2	EBI-78035,EBI-494118	From a different organism.
Dnm1l	O35303	1	EBI-287195,EBI-1767447	From a different organism.
HRK	O00198	1	EBI-78035,EBI-701322
HRK	O00198	2	EBI-287195,EBI-701322
NLRP1	Q9C000	4	EBI-78035,EBI-1220518
PPP1CA	P62136	1	EBI-78035,EBI-357253
PPP1CC	P36873-1	1	EBI-78035,EBI-356289
SIVA1	O15304	1	EBI-78035,EBI-520756
SIVA1	O15304	1	EBI-287195,EBI-520756
SIVA1	O15304-1	3	EBI-287195,EBI-520766
SPNS1	Q9H2V7	2	EBI-78035,EBI-1386527
TP53	P04637	2	EBI-287195,EBI-366083
Tp53	P02340	2	EBI-287195,EBI-474016	From a different organism.

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]

Isoform Bcl-X(L) (identifier: Q07817-1)

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 Bcl-X(S) (identifier: Q07817-2)

The sequence of this isoform differs from the canonical sequence as follows:
     126-188: Missing.

Isoform Bcl-X(beta) (identifier: Q07817-3)

The sequence of this isoform differs from the canonical sequence as follows:
     189-233: DTFVELYGNN...VLLGSLFSRK → VRTKPLVCPF...CWVIVGDVDS

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 233

233

Apoptosis regulator Bcl-X

PRO_0000143062

Regions

Transmembrane

210 – 226

17

Potential

Motif

4 – 24

21

BH4

Motif

86 – 100

15

BH3

Motif

129 – 148

20

BH1

Motif

180 – 195

16

BH2

Sites

Site

61 – 62

2

Cleavage; by caspase-1

Natural variations

Alternative sequence

126 – 188

63

Missing in isoform Bcl-X(S).

VSP_000515

Alternative sequence

189 – 233

45

DTFVE…LFSRK → VRTKPLVCPFSLASGQRSPT ALLLYLFLLCWVIVGDVDS in isoform Bcl-X(beta).

VSP_000516

Experimental info

Mutagenesis

61

1

D → A: No cleavage by caspase-1 nor by caspase-3

Mutagenesis

131 – 133

3

FRD → VRA: No heterodimerization with BAX

Mutagenesis

135 – 137

3

VNW → AIL: Loss of anti-apoptotic activity

Mutagenesis

138 – 140

3

GRI → ELN: Loss of anti-apoptotic activity

Mutagenesis

138

1

G → A: No heterodimerization with BAX

Mutagenesis

148

1

G → E: No heterodimerization with BAX

Mutagenesis

156

1

D → A: No effect on caspase-1 cleavage

Mutagenesis

176

1

D → A: No effect on caspase-1 cleavage

Mutagenesis

188 – 189

2

WD → GA: Reduces anti-apoptotic activity by about half

Mutagenesis

189

1

D → A: No effect on caspase-1 cleavage

Sequence conflict

70

1

G → A in CAA80661. Ref.1

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

233

Helix Strand Turn

Details...

Helix

2 – 19

18

Helix

83 – 100

18

Helix

106 – 112

7

Helix

120 – 127

8

Helix

128 – 131

4

Helix

137 – 156

20

Helix

162 – 177

16

Helix

179 – 184

6

Turn

185 – 187

3

Helix

188 – 195

8

Sequences

	Sequence		Length	Mass (Da)
	Isoform Bcl-X(L) [UniParc]. Last modified February 1, 1995. Version 1. Checksum: E09D3CDD851AE9BE	FASTA	233	26,049
	10 20 30 40 50 60 MSQSNRELVV DFLSYKLSQK GYSWSQFSDV EENRTEAPEG TESEMETPSA INGNPSWHLA 70 80 90 100 110 120 DSPAVNGATG HSSSLDAREV IPMAAVKQAL REAGDEFELR YRRAFSDLTS QLHITPGTAY 130 140 150 160 170 180 QSFEQVVNEL FRDGVNWGRI VAFFSFGGAL CVESVDKEMQ VLVSRIAAWM ATYLNDHLEP 190 200 210 220 230 WIQENGGWDT FVELYGNNAA AESRKGQERF NRWFLTGMTV AGVVLLGSLF SRK
	Isoform Bcl-X(S) [UniParc]. Checksum: 75D1FC01EC06AD47		170	18,894
	10 20 30 40 50 60 MSQSNRELVV DFLSYKLSQK GYSWSQFSDV EENRTEAPEG TESEMETPSA INGNPSWHLA 70 80 90 100 110 120 DSPAVNGATG HSSSLDAREV IPMAAVKQAL REAGDEFELR YRRAFSDLTS QLHITPGTAY 130 140 150 160 170 QSFEQDTFVE LYGNNAAAES RKGQERFNRW FLTGMTVAGV VLLGSLFSRK
	Isoform Bcl-X(beta) [UniParc]. Checksum: 1EF621E5D0744E4E		227	25,290
	10 20 30 40 50 60 MSQSNRELVV DFLSYKLSQK GYSWSQFSDV EENRTEAPEG TESEMETPSA INGNPSWHLA 70 80 90 100 110 120 DSPAVNGATG HSSSLDAREV IPMAAVKQAL REAGDEFELR YRRAFSDLTS QLHITPGTAY 130 140 150 160 170 180 QSFEQVVNEL FRDGVNWGRI VAFFSFGGAL CVESVDKEMQ VLVSRIAAWM ATYLNDHLEP 190 200 210 220 WIQENGGWVR TKPLVCPFSL ASGQRSPTAL LLYLFLLCWV IVGDVDS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death." Boise L.H., Gonzalez-Garcia M., Postema C.E., Ding L., Lindsten T., Turka L.A., Mao X., Nunez G., Thompson C.B. Cell 74:597-608(1993) [PubMed: 8358789] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS BCL-X(L) AND BCL-X(S)).
[2]	Inohara N., Ohta S. Submitted (OCT-1996) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM BCL-X(BETA)).
[3]	"Identification of a human cDNA encoding a novel Bcl-x isoform." Ban J., Eckhart L., Weninger W., Mildner M., Tschachler E. Biochem. Biophys. Res. Commun. 248:147-152(1998) [PubMed: 9675101] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM BCL-X(BETA)).
[4]	"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 (OCT-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM BCL-X(L)).
[5]	"The DNA sequence and comparative analysis of human chromosome 20." Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R., Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L., Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M., Beasley O.P., Bird C.P., Blakey S.E. , Bridgeman A.M., Brown A.J., Buck D., Burrill W.D., Butler A.P., Carder C., Carter N.P., Chapman J.C., Clamp M., Clark G., Clark L.N., Clark S.Y., Clee C.M., Clegg S., Cobley V.E., Collier R.E., Connor R.E., Corby N.R., Coulson A., Coville G.J., Deadman R., Dhami P.D., Dunn M., Ellington A.G., Frankland J.A., Fraser A., French L., Garner P., Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E., Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J., Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D., Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S., Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D., Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A., Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T., Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I., Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H., Rice C.M., Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., Skuce C.D., Smith M.L., Soderlund C., Steward C.A., Sulston J.E., Swann R.M., Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., Tracey A., Tromans A.C., Vaudin M., Wall M., Wallis J.M., Whitehead S.L., Whittaker P., Willey D.L., Williams L., Williams S.A., Wilming L., Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., Rogers J. Nature 414:865-871(2001) [PubMed: 11780052] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	"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 BCL-X(L)). Tissue: Lung.
[7]	"Multiple Bcl-2 family members demonstrate selective dimerizations with Bax." Sedlak T.W., Oltvai Z.N., Yang E., Wang K., Boise L.H., Thompson C.B., Korsmeyer S.J. Proc. Natl. Acad. Sci. U.S.A. 92:7834-7838(1995) [PubMed: 7644501] [Abstract] Cited for: MUTAGENESIS OF GLY-138, HETERODIMERIZATION.
[8]	"Bax-independent inhibition of apoptosis by Bcl-XL." Cheng E.H.-Y., Levine B., Boise L.H., Thompson C.B., Hardwick J.M., Korsmeyer S.J. Nature 379:554-556(1996) [PubMed: 8596636] [Abstract] Cited for: MUTAGENESIS OF BH1 AND BH2 MOTIFS.
[9]	"Modulation of cell death by Bcl-xL through caspase interaction." Clem R.J., Cheng E.H.-Y., Karp C.L., Kirsch D.G., Ueno K., Takahashi A., Kastan M.B., Griffin D.E., Earnshaw W.C., Veliuona M.A., Hardwick J.M. Proc. Natl. Acad. Sci. U.S.A. 95:554-559(1998) [PubMed: 9435230] [Abstract] Cited for: CLEAVAGE BY CASPASES, MUTAGENESIS OF ASP-61.
[10]	"PUMA induces the rapid apoptosis of colorectal cancer cells." Yu J., Zhang L., Hwang P.M., Kinzler K.W., Vogelstein B. Mol. Cell 7:673-682(2001) [PubMed: 11463391] [Abstract] Cited for: INTERACTION WITH BCL2 AND BBC3.
[11]	"Siva-1 binds to and inhibits BCL-X(L)-mediated protection against UV radiation-induced apoptosis." Xue L., Chu F., Cheng Y., Sun X., Borthakur A., Ramarao M., Pandey P., Wu M., Schlossman S.F., Prasad K.V.S. Proc. Natl. Acad. Sci. U.S.A. 99:6925-6930(2002) [PubMed: 12011449] [Abstract] Cited for: INTERACTION WITH SIVA.
[12]	"PGAM5, a Bcl-XL-interacting protein, is a novel substrate for the redox-regulated Keap1-dependent ubiquitin ligase complex." Lo S.-C., Hannink M. J. Biol. Chem. 281:37893-37903(2006) [PubMed: 17046835] [Abstract] Cited for: INTERACTION WITH PGAM5.
[13]	"X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death." Muchmore S.W., Sattler M., Liang H., Meadows R.P., Harlan J.E., Yoon H.S., Nettesheim D., Chang B.S., Thompson C.B., Wong S.L., Ng S.L., Fesik S.W. Nature 381:335-341(1996) [PubMed: 8692274] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS), STRUCTURE BY NMR OF 1-209.
[14]	"Structure of Bcl-xL-Bak peptide complex: recognition between regulators of apoptosis." Sattler M., Liang H., Nettesheim D., Meadows R.P., Harlan J.E., Eberstadt M., Yoon H.S., Shuker S.B., Chang B.S., Minn A.J., Thompson C.B., Fesik S.W. Science 275:983-986(1997) [PubMed: 9020082] [Abstract] Cited for: STRUCTURE BY NMR OF 1-209.
[15]	"Rationale for Bcl-xL/Bad peptide complex formation from structure, mutagenesis, and biophysical studies." Petros A.M., Nettesheim D.G., Wang Y., Olejniczak E.T., Meadows R.P., Mack J., Swift K., Matayoshi E.D., Zhang H., Thompson C.B., Fesik S.W. Protein Sci. 9:2528-2534(2000) [PubMed: 11206074] [Abstract] Cited for: STRUCTURE BY NMR OF 1-209 IN COMPLEX WITH BAD.
[16]	"Bcl-XL mutations suppress cellular sensitivity to antimycin A." Manion M.K., O'Neill J.W., Giedt C.D., Kim K.M., Zhang K.Y.Z., Hockenbery D.M. J. Biol. Chem. 279:2159-2165(2004) [PubMed: 14534311] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) OF 1-211.
[17]	"An inhibitor of Bcl-2 family proteins induces regression of solid tumours." Oltersdorf T., Elmore S.W., Shoemaker A.R., Armstrong R.C., Augeri D.J., Belli B.A., Bruncko M., Deckwerth T.L., Dinges J., Hajduk P.J., Joseph M.K., Kitada S., Korsmeyer S.J., Kunzer A.R., Letai A., Li C., Mitten M.J., Nettesheim D.G. , Ng S.-C., Nimmer P.M., O'Connor J.M., Oleksijew A., Petros A.M., Reed J.C., Shen W., Tahir S.K., Thompson C.B., Tomaselli K.J., Wang B., Wendt M.D., Zhang H., Fesik S.W., Rosenberg S.H. Nature 435:677-681(2005) [PubMed: 15902208] [Abstract] Cited for: STRUCTURE BY NMR OF 1-209.
[18]	"BCL-XL dimerization by three-dimensional domain swapping." O'Neill J.W., Manion M.K., Maguire B., Hockenbery D.M. J. Mol. Biol. 356:367-381(2006) [PubMed: 16368107] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (3.45 ANGSTROMS) OF 1-211, SUBUNIT.
[19]	"Crystal structure of the Bcl-XL-Beclin 1 peptide complex: Beclin 1 is a novel BH3-only protein." Oberstein A., Jeffrey P.D., Shi Y. J. Biol. Chem. 282:13123-13132(2007) [PubMed: 17337444] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 83-209 IN COMPLEX WITH BECN1.
[20]	"Studies leading to potent, dual inhibitors of Bcl-2 and Bcl-xL." Bruncko M., Oost T.K., Belli B.A., Ding H., Joseph M.K., Kunzer A., Martineau D., McClellan W.J., Mitten M., Ng S.-C., Nimmer P.M., Oltersdorf T., Park C.-M., Petros A.M., Shoemaker A.R., Song X., Wang X., Wendt M.D. , Zhang H., Fesik S.W., Rosenberg S.H., Elmore S.W. J. Med. Chem. 50:641-662(2007) [PubMed: 17256834] [Abstract] Cited for: STRUCTURE BY NMR OF 1-209.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBLGenBankDDBJ	Z23116<