BH4

BH4 Bcl-2 homology region 4

• SMART accession number: SM00265
• Description: -
• Interpro abstract (IPR003093):

  Apoptosis, or programmed cell death (PCD), is a common and evolutionarily conserved property of all metazoans [ (PUBMED:11341280) ]. In many biological processes, apoptosis is required to eliminate supernumerary or dangerous (such as pre-cancerous) cells and to promote normal development. Dysregulation of apoptosis can, therefore, contribute to the development of many major diseases including cancer, autoimmunity and neurodegenerative disorders. In most cases, proteins of the caspase family execute the genetic programme that leads to cell death.

  Bcl-2 proteins are central regulators of caspase activation, and play a key role in cell death by regulating the integrity of the mitochondrial and endoplasmic reticulum (ER) membranes [ (PUBMED:12631689) ]. At least 20 Bcl-2 proteins have been reported in mammals, and several others have been identified in viruses. Bcl-2 family proteins fall roughly into three subtypes, which either promote cell survival (anti-apoptotic) or trigger cell death (pro-apoptotic). All members contain at least one of four conserved motifs, termed Bcl-2 Homology (BH) domains. Bcl-2 subfamily proteins, which contain at least BH1 and BH2, promote cell survival by inhibiting the adapters needed for the activation of caspases.

  Pro-apoptotic members potentially exert their effects by displacing the adapters from the pro-survival proteins; these proteins belong either to the Bax subfamily, which contain BH1-BH3, or to the BH3 subfamily, which mostly only feature BH3 [ (PUBMED:9735050) ]. Thus, the balance between antagonistic family members is believed to play a role in determining cell fate. Members of the wider Bcl-2 family, which also includes Bcl-x, Bcl-w and Mcl-1, are described by their similarity to Bcl-2 protein, a member of the pro-survival Bcl-2 subfamily [ (PUBMED:9735050) ]. Full-length Bcl-2 proteins feature all four BH domains, seven alpha-helices, and a C-terminal hydrophobic motif that targets the protein to the outer mitochondrial membrane, ER and nuclear envelope.

  Active cell suicide (apoptosis) is induced by events such as growth factor withdrawal and toxins. It is controlled by regulators, which have either an inhibitory effect on programmed cell death (anti-apoptotic) or block the protective effect of inhibitors (pro-apoptotic) [ (PUBMED:15335822) (PUBMED:8918887) ]. Many viruses have found a way of countering defensive apoptosis by encoding their own anti-apoptosis genes preventing their target-cells from dying too soon.

  All proteins belonging to the Bcl-2 family [ (PUBMED:8910675) ] contain either a BH1, BH2, BH3, or BH4 domain. All anti-apoptotic proteins contain BH1 and BH2 domains, some of them contain an additional N-terminal BH4 domain (Bcl-2, Bcl-x(L), Bcl-w), which is never seen in pro-apoptotic proteins, except for Bcl-x(S). On the other hand, all pro-apoptotic proteins contain a BH3 domain (except for Bad) necessary for dimerisation with other proteins of Bcl-2 family and crucial for their killing activity, some of them also contain BH1 and BH2 domains (Bax, Bak). The BH3 domain is also present in some anti-apoptotic protein, such as Bcl-2 or Bcl-x(L). Proteins that are known to contain these domains include vertebrate Bcl-2 (alpha and beta isoforms) and Bcl-x (isoforms (Bcl-x(L) and Bcl-x(S)); mammalian proteins Bax and Bak; mouse protein Bid; Xenopus laevis proteins Xr1 and Xr11; human induced myeloid leukemia cell differentiation protein MCL1 and Caenorhabditis elegans protein ced-9.

• GO process: regulation of apoptotic process (GO:0042981)

There are 655 BH4 domains in 655 proteins in SMART's nrdb database.

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

SwissProt sequences and OMIM curated human diseases associated with missense mutations within the BH4 domain.

Protein	Disease
Apoptosis regulator Bcl-2 (P10415) (SMART)	OMIM:151430: Leukemia/lymphoma, B-cell, 2

Metabolism (metabolic pathways involving proteins which contain this domain)

% proteins involved	KEGG pathway ID	Description
15.38	map05222	Small cell lung cancer
15.38	map05030	Amyotrophic lateral sclerosis (ALS)
15.38	map04210	Apoptosis
7.69	map05210	Colorectal cancer
7.69	map05060	Prion disease
7.69	map05212	Pancreatic cancer
7.69	map04630	Jak-STAT signaling pathway
7.69	map05220	Chronic myeloid leukemia
7.69	map04510	Focal adhesion
7.69	map05215	Prostate cancer

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 BH4 domain which could be assigned to a KEGG orthologous group, and not all proteins containing BH4 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 BH4 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
1g5j	COMPLEX OF BCL-XL WITH PEPTIDE FROM BAD
1g5m	HUMAN BCL-2, ISOFORM 1
1gjh	HUMAN BCL-2, ISOFORM 2
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
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
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
2lp8	SOLUTION STRUCTURE OF AN APOPTOSIS ACTIVATING PHOTOSWITCHABLE BAK PEPTIDE BOUND to BCL-XL
2lpc	NMR STRUCTURE of Bcl-XL
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
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
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
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
2yxj	Crystal structure of Bcl-xL in complex with ABT-737
3cva	Human Bcl-xL containing a Trp to Ala mutation at position 137
3fdl	Bim BH3 peptide in complex with Bcl-xL
3fdm	alpha/beta foldamer in complex with Bcl-xL
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
3pl7	Crystal structure of Bcl-xL in complex with the BaxBH3 domain
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
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
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
4hnj	Crystallographic structure of BCL-xL domain-swapped dimer in complex with PUMA BH3 peptide at 2.9A resolution
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
4ppi	4PPI
4qnq	4QNQ
4qve	4QVE
4qvf	4QVF
4qvx	4QVX
4tuh	4TUH
4yj4	4YJ4
4yk9	4YK9
4z9v	4Z9V
5agw	5AGW
5agx	5AGX
5c3g	5C3G
5fcg	5FCG
5fmj	5FMJ
5fmk	5FMK
5jsn	5JSN

Links (links to other resources describing this domain)

• INTERPRO: IPR003093
• PROSITE: BH4_2