The domain within your query sequence starts at position 46 and ends at position 144; the E-value for the BCL domain shown below is 1.22e-45.

MRAAGDEFETRFRRTFSDLAAQLHVTPGSAQQRFTQVSDELFQGGPNWGRLVAFFVFGAA
LCAESVNKEMEPLVGQVQDWMVAYLETRLADWIHSSGGW

BCL

BCL (B-Cell lymphoma); contains BH1, BH2 regions

• SMART accession number: SM00337
• Description: (BH1, BH2, (BH3 (one helix only)) and not BH4(one helix only)). Involved in apoptosis regulation

There are 4976 BCL domains in 4959 proteins in SMART's nrdb database.

Literature (relevant references for this domain)

Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.

• Muchmore SW et al.
• X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death.
• Nature. 1996; 381: 335-41

THE Bcl-2 family of proteins regulate programmed cell death by an unknown mechanism. Here we describe the crystal and solution structures of a Bcl-2 family member, Bcl-xL (ref. 2). The structures consist of two central, primarily hydrophobic alpha-helices, which are surrounded by amphipathic helices. A 60-residue loop connecting helices alpha1 and alpha2 was found to be flexible and non-essential for anti-apoptotic activity. The three functionally important Bcl-2 homology regions (BH1, BH2 and BH3) are in close spatial proximity and form an elongated hydrophobic cleft that may represent the binding site for other Bcl-2 family members. The arrangement of the alpha-helices in Bcl-xL is reminiscent of the membrane translocation domain of bacterial toxins, in particular diphtheria toxin and the colicins. The structural similarity may provide a clue to the mechanism of action of the Bcl-2 family of proteins.

• Reed JC, Zha H, Aime-Sempe C, Takayama S, Wang HG
• Structure-function analysis of Bcl-2 family proteins. Regulators of programmed cell death.
• Adv Exp Med Biol. 1996; 406: 99-112

The Bcl-2 protein blocks a distal step in an evolutionarily conserved pathway for programmed cell death and apoptosis. To gain better understanding of how this protein functions, we have undertaken a structure-function analysis of this protein, focusing on domains within Bcl-2 that are required for function and for interactions with other proteins. Four conserved domains are present in Bcl-2 and several of its homologs: BH1 (residues 136-155), BH2 (187-202), BH3 (93-107) and BH4 (10-30). Deletion of the BH1, BH2, or BH4 domains of Bcl-2 abolishes its ability to suppress cell death in mammalian cells and prevents homodimerization of these mutant proteins, though these mutants can still bind to the wild-type Bcl-2 protein. These mutants also fail to bind to BAG-1 and Raf-1, two proteins that we have shown can associate with protein complexes containing Bcl-2 and which cooperate with Bcl-2 to suppress cell death. Deletion of either BH1 or BH2 nullifies the ability of Bcl-2 to: (a) suppress death in mammalian cells: (b) block Bax-induced lethality in yeast; and (c) heterodimerize with Bax. In contrast, deletion of the BH4 domain of Bcl-2 nullifies anti-apoptotic function and homodimerization, but does not impair binding to the pro-apoptotic protein Bax. Taken together, the data suggest the possibility that both Bcl-2/Bcl-2 homodimerization and Bcl-2/Bax heterodimerization are necessary but insufficient for the anti-apoptotic function of the Bcl-2 protein. Homodimerization of Bcl-2 with itself involves a head-to-tail interaction, in which an N-terminal domain where BH4 resides interacts with the more distal region of Bcl-2 where BH1, BH2, and BH3 are located. In contrast, Bcl-2/Bax heterodimerization involves a tail-to-tail interaction, that requires the portion of Bcl-2 where BH1, BH2, and BH3 reside and a central region in Bax where the BH3 domain is located. The BH3 domain of Bax is also required for Bax/Bax homodimerization and pro-apoptotic function in both yeast and mammalian cells. Thus, Bcl-2 may suppress cell death at least in part by binding to Bax via the BH3 domain and thereby preventing formation of Bax/Bax homodimers. Further studies however are required to delineate the full significance of Bcl-2/Bcl-2, Bcl-2/Bax, and Bax/Bax dimers and the biochemical mechanisms by which Bcl-2 family proteins ultimately control cell life and death.

• Vaux DL
• Toward an understanding of the molecular mechanisms of physiological cell death.
• Proc Natl Acad Sci U S A. 1993; 90: 786-9

Cell death is a normal physiological process. Morphological studies have shown that cells that die by physiological mechanisms often undergo characteristic changes termed "apoptosis" or "programmed cell death." Recent work has begun to unravel the molecular mechanisms of these deaths and has shown that one of the primary cell-death pathways is conserved throughout much of evolution. In the nematode Caenorhabditis elegans programmed cell deaths are mediated by a mechanism controlled by the ced-9 gene; in mammals apoptosis can often be inhibited by expression of the bcl-2 gene. The ability of the human BCL2 gene to prevent cell deaths in C. elegans strongly suggests that bcl-2 and ced-9 are homologous genes. Although the process of cell death controlled by bcl-2 can occur in many cell types, there appears to be more than one physiological cell-death mechanism. Targets of cytotoxic T cells and cells deprived of growth factor both exhibit changes characteristic of apoptosis, such as DNA degradation. However, bcl-2 expression protects cells from factor withdrawal but fails to prevent cytotoxic T-cell killing. DNA degradation is, thus, not specific for any one cell-death mechanism. The ability of bcl-2 to protect cells from a wide variety of pathological, as well as physiological, stimuli indicates that many triggers can serve to activate the same suicide pathway, even some thought to cause necrosis, and not physiological cell death.

Disease (disease genes where sequence variants are found in this domain)

SwissProt sequences and OMIM curated human diseases associated with missense mutations within the BCL domain.

Protein	Disease
UNKNOWN (SMART)	OMIM:600040: Colorectal cancer ; T-cell acute lymphoblastic leukemia

Metabolism (metabolic pathways involving proteins which contain this domain)

% proteins involved	KEGG pathway ID	Description
16.55	map05030	Amyotrophic lateral sclerosis (ALS)
16.55	map04210	Apoptosis
10.79	map05222	Small cell lung cancer
10.07	map05210	Colorectal cancer
6.47	map05212	Pancreatic cancer
6.47	map04630	Jak-STAT signaling pathway
6.47	map05220	Chronic myeloid leukemia
5.76	map05040	Huntington's disease
5.76	map04115	p53 signaling pathway
4.32	map05060	Prion disease
4.32	map04510	Focal adhesion
4.32	map05215	Prostate cancer
1.44	map01040	Biosynthesis of unsaturated fatty acids
0.72	map00190	Oxidative phosphorylation

This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with BCL domain which could be assigned to a KEGG orthologous group, and not all proteins containing BCL domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.

Structure (3D structures containing this domain)

3D Structures of BCL domains in PDB

PDB code	Title
1af3	RAT BCL-XL AN APOPTOSIS INHIBITORY PROTEIN
1bxl	STRUCTURE OF BCL-XL/BAK PEPTIDE COMPLEX, NMR, MINIMIZED AVERAGE STRUCTURE
1f16	SOLUTION STRUCTURE OF A PRO-APOPTOTIC PROTEIN BAX
1g5j	COMPLEX OF BCL-XL WITH PEPTIDE FROM BAD
1g5m	HUMAN BCL-2, ISOFORM 1
1gjh	HUMAN BCL-2, ISOFORM 2
1k3k	Solution Structure of a Bcl-2 Homolog from Kaposi's Sarcoma Virus
1lxl	NMR STRUCTURE OF BCL-XL, AN INHIBITOR OF PROGRAMMED CELL DEATH, MINIMIZED AVERAGE STRUCTURE
1maz	X-RAY STRUCTURE OF BCL-XL, AN INHIBITOR OF PROGRAMMED CELL DEATH
1mk3	SOLUTION STRUCTURE OF HUMAN BCL-W PROTEIN
1o0l	THE STRUCTURE OF BCL-W REVEALS A ROLE FOR THE C-TERMINAL RESIDUES IN MODULATING BIOLOGICAL ACTIVITY
1ohu	Structure of Caenorhabditis elegans CED-9
1pq0	Crystal structure of mouse Bcl-xl
1pq1	Crystal structure of Bcl-xl/Bim
1r2d	Structure of Human Bcl-XL at 1.95 Angstroms
1r2e	Human Bcl-XL containing a Glu to Leu mutation at position 92
1r2g	Human Bcl-XL containing a Phe to Trp mutation at position 97
1r2h	Human Bcl-XL containing an Ala to Leu mutation at position 142
1r2i	Human Bcl-XL containing a Phe to Leu mutation at position 146
1ty4	Crystal structure of a CED-9/EGL-1 complex
1wsx	Solution structure of MCL-1
1ysg	Solution Structure of the Anti-apoptotic Protein Bcl-xL in Complex with ""SAR by NMR"" Ligands
1ysi	Solution structure of the anti-apoptotic protein Bcl-xL in complex with an acyl-sulfonamide-based ligand
1ysn	Solution structure of the anti-apoptotic protein Bcl-xL complexed with an acyl-sulfonamide-based ligand
1ysw	Solution structure of the anti-apoptotic protein Bcl-2 complexed with an acyl-sulfonamide-based ligand
1yxm	Crystal structure of peroxisomal trans 2-enoyl CoA reductase
1zy3	Structural model of complex of Bcl-w protein with Bid BH3-peptide
2a5y	Structure of a CED-4/CED-9 complex
2b48	Bcl-XL 3D Domain Swapped Dimer
2bzw	The crystal structure of BCL-XL in complex with full-length BAD
2ims	The X-ray Structure of a Bak Homodimer Reveals an Inhibitory Zinc Binding Site
2imt	The X-ray Structure of a Bak Homodimer Reveals an Inhibitory Zinc Binding Site
2jcn	The crystal structure of BAK1 - a mitochondrial apoptosis regulator
2jm6	Solution structure of MCL-1 complexed with NOXAB
2k7w	BAX Activation is Initiated at a Novel Interaction Site
2kbw	Solution Structure of human Mcl-1 complexed with human Bid_BH3 peptide
2kua	Solution structure of a divergent Bcl-2 protein
2lp8	SOLUTION STRUCTURE OF AN APOPTOSIS ACTIVATING PHOTOSWITCHABLE BAK PEPTIDE BOUND to BCL-XL
2lpc	NMR STRUCTURE of Bcl-XL
2lr1	Structural Mechanism for Bax Inhibition by Cytomegalovirus Protein vMIA
2m03	Solution structure of BCL-xL determined with selective isotope labelling of I,L,V sidechains
2m04	Solution structure of BCL-xL in complex with PUMA BH3 peptide
2m5b	The NMR structure of the BID-BAK complex
2me8	Solution Structure of BCL-xL in its p53-bound conformation determined with selective isotope labelling of I,L,V sidechains
2me9	Solution structure of BCL-xL containing the alpha1-alpha2 disordered loop determined with selective isotope labelling of I,L,V sidechains
2mej	Solution Structure of the Complex Between BCL-xL and the p53 Core Domain determined with PRE restraints
2mhs	NMR Structure of human Mcl-1
2nl9	Crystal structure of the Mcl-1:Bim BH3 complex
2nla	Crystal structure of the Mcl-1:mNoxaB BH3 complex
2o1y	Solution structure of the anti-apoptotic protein Bcl-xL in complex with an acyl-sulfonamide-based ligand
2o21	Solution structure of the anti-apoptotic protein Bcl-2 in complex with an acyl-sulfonamide-based ligand
2o22	Solution structure of the anti-apoptotic protein Bcl-2 in complex with an acyl-sulfonamide-based ligand
2o2f	Solution structure of the anti-apoptotic protein Bcl-2 in complex with an acyl-sulfonamide-based ligand
2o2m	Solution structure of the anti-apoptotic protein Bcl-xL in complex with an acyl-sulfonamide-based ligand
2o2n	Solution structure of the anti-apoptotic protein Bcl-xL in complex with an acyl-sulfonamide-based ligand
2p1l	Structure of the Bcl-XL:Beclin 1 complex
2pon	Solution structure of the Bcl-xL/Beclin-1 complex
2pqk	X-ray crystal structure of human Mcl-1 in complex with Bim BH3
2roc	Solution structure of Mcl-1 Complexed with Puma
2rod	Solution Structure of MCL-1 Complexed with NoxaA
2vm6	HUMAN BCL-2A1 in complex with BIM
2vof	Structure of mouse A1 bound to the Puma BH3-domain
2vog	Structure of mouse A1 bound to the Bmf BH3-domain
2voh	Structure of mouse A1 bound to the Bak BH3-domain
2voi	Structure of mouse A1 bound to the Bid BH3-domain
2w3l	Crystal Structure of Chimaeric Bcl2-xL and Phenyl Tetrahydroisoquinoline Amide Complex
2xa0	Crystal structure of BCL-2 in complex with a BAX BH3 peptide
2y6w	Structure of a Bcl-w dimer
2yj1	Puma BH3 foldamer in complex with Bcl-xL
2yq6	Structure of Bcl-xL bound to BimSAHB
2yq7	Structure of Bcl-xL bound to BimLOCK
2yv6	Crystal structure of human Bcl-2 family protein Bak
2yxj	Crystal structure of Bcl-xL in complex with ABT-737
3cva	Human Bcl-xL containing a Trp to Ala mutation at position 137
3d7v	Crystal structure of Mcl-1 in complex with an Mcl-1 selective BH3 ligand
3fdl	Bim BH3 peptide in complex with Bcl-xL
3fdm	alpha/beta foldamer in complex with Bcl-xL
3i1h	Crystal structure of human BFL-1 in complex with BAK BH3 peptide
3ihc	Crystal structure of mouse Bcl-xl (wt) at pH 5.0
3ihd	Crystal structure of mouse Bcl-xl mutant (Y101A) at pH 5.0
3ihe	Crystal structure of mouse Bcl-xl mutant (F105A) at pH 6.0
3ihf	Crystal structure of mouse Bcl-xl mutant (R139A) at pH 5.0
3iig	Crystal structure of mouse Bcl-xl mutant (F105A) at pH 5.0
3iih	Crystal structure of mouse Bcl-xl (wt) at pH 6.0
3ilb	Crystal structure of mouse Bcl-xl mutant (R139A) at pH 6.0
3ilc	Crystal structure of mouse Bcl-xl mutant (Y101A) at pH 6.0
3inq	Crystal structure of BCL-XL in complex with W1191542
3io8	BimL12F in complex with Bcl-xL
3io9	BimL12Y in complex with Mcl-1
3kj0	Mcl-1 in complex with Bim BH3 mutant I2dY
3kj1	Mcl-1 in complex with Bim BH3 mutant I2dA
3kj2	Mcl-1 in complex with Bim BH3 mutant F4aE
3kz0	MCL-1 complex with MCL-1-specific selected peptide
3mk8	The MCL-1 BH3 Helix is an Exclusive MCL-1 Inhibitor and Apoptosis Sensitizer
3mqp	Crystal Structure of human BFL-1 in complex with NOXA BH3 peptide, Northeast Structural Genomics Consortium Target HR2930
3pk1	Crystal structure of Mcl-1 in complex with the BaxBH3 domain
3pl7	Crystal structure of Bcl-xL in complex with the BaxBH3 domain
3qbr	BakBH3 in complex with sjA
3qkd	Crystal structure of Bcl-xL in complex with a Quinazoline sulfonamide inhibitor
3r85	Crystal structure of human SOUL BH3 domain in complex with Bcl-xL
3sp7	Crystal Structure of Bcl-xL bound to BM903
3spf	Crystal Structure of Bcl-xL bound to BM501
3wix	Crystal structure of Mcl-1 in complex with compound 4
3wiy	Crystal structure of Mcl-1 in complex with compound 10
3wiz	Crystal structure of Bcl-xL in complex with compound 10
3zk6	Crystal structure of Bcl-xL in complex with inhibitor (Compound 2).
3zln	Crystal structure of Bcl-xL in complex with inhibitor (Compound 3).
3zlo	Crystal structure of Bcl-xL in complex with inhibitor (Compound 6).
3zlr	Crystal structure of Bcl-xL in complex with inhibitor (WEHI-539).
4a1u	Crystal structure of alpha-beta-foldamer 2c in complex with Bcl-xL
4a1w	Crystal structure of alpha-beta foldamer 4c in complex with Bcl-xL
4aq3	HUMAN BCL-2 WITH PHENYLACYLSULFONAMIDE INHIBITOR
4b4s	Crystal Structure of a pro-survival Bcl-2:Bim BH3 complex
4bd2	Bax domain swapped dimer in complex with BidBH3
4bd6	Bax domain swapped dimer in complex with BaxBH3
4bd7	Bax domain swapped dimer induced by octylmaltoside
4bd8	Bax domain swapped dimer induced by BimBH3 with CHAPS
4bdu	Bax BH3-in-Groove dimer (GFP)
4bpi	Mcl-1 bound to alpha beta Puma BH3 peptide 2
4bpj	Mcl-1 bound to alpha beta Puma BH3 peptide 3
4bpk	Bcl-xL bound to alpha beta Puma BH3 peptide 5
4c52	Crystal structure of Bcl-xL in complex with benzoylurea compound (39b)
4c5d	Crystal structure of Bcl-xL in complex with benzoylurea compound (42)
4cim	4CIM
4cin	4CIN
4ehr	Crystal structure of Bcl-Xl complex with 4-(5-butyl-3-(hydroxymethyl)-1-phenyl-1h-pyrazol-4-yl)-3-(3,4-dihydro-2(1h)-isoquinolinylcarbonyl)-n-((2-(trimethylsilyl)ethyl)sulfonyl)benzamide
4g35	Mcl-1 in complex with a biphenyl cross-linked Noxa peptide.
4hnj	Crystallographic structure of BCL-xL domain-swapped dimer in complex with PUMA BH3 peptide at 2.9A resolution
4hw2	Discovery of potent Mcl-1 inhibitors using fragment-based methods and structure-based design
4hw3	Discovery of potent Mcl-1 inhibitors using fragment-based methods and structure-based design
4hw4	Discovery of potent Mcl-1 inhibitors using fragment-based methods and structure-based design
4ieh	Crystal Structure of human Bcl-2 in complex with a small molecule inhibitor targeting Bcl-2 BH3 domain interactions
4k5a	Co-crystallization with conformation-specific designed ankyrin repeat proteins explains the conformational flexibility of BCL-W
4k5b	Co-crystallization with conformation-specific designed ankyrin repeat proteins explains the conformational flexibility of BCL-W
4lvt	Bcl_2-Navitoclax (ABT-263) Complex
4lxd	Bcl_2-Navitoclax Analog (without Thiophenyl) Complex
4man	Bcl_2-Navitoclax Analog (with Indole) Complex
4oq5	Crystal Structure of Human MCL-1 Bound to Inhibitor 4-(4-methylnaphthalen-1-yl)-2-{[(4-phenoxyphenyl)sulfonyl]amino}benzoic acid
4oq6	Crystal Structure of Human MCL-1 Bound to Inhibitor 4-hydroxy-4'-propylbiphenyl-3-carboxylic acid
4ppi	4PPI
4qnq	4QNQ
4qve	4QVE
4qvf	4QVF
4qvx	4QVX
4s0o	4S0O
4s0p	4S0P
4tuh	4TUH
4u2u	4U2U
4u2v	4U2V
4wgi	4WGI
4wmr	4WMR
4wms	4WMS
4wmt	4WMT
4wmu	4WMU
4wmv	4WMV
4wmw	4WMW
4wmx	4WMX
4yj4	4YJ4
4yk9	4YK9
4z9v	4Z9V
4zbf	4ZBF
4zbi	4ZBI
4zeq	4ZEQ
4zie	4ZIE
4zif	4ZIF
4zig	4ZIG
4zih	4ZIH
4zii	4ZII
5agw	5AGW
5agx	5AGX
5c3f	5C3F
5c3g	5C3G
5c6h	5C6H
5fc4	5FC4
5fcg	5FCG
5fdo	5FDO
5fdr	5FDR
5fmi	5FMI
5fmj	5FMJ
5fmk	5FMK
5jsb	5JSB
5jsn	5JSN
5ktg	5KTG
5lof	5LOF

Links (links to other resources describing this domain)

• PROSITE: BCL2_FAMILY
• PFAM: Bcl-2