l2
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SMART

Letunic et al. (2017) Nucleic Acids Res doi: 10.1093/nar/gkx922Nucleic Acids Res doi: 10.1093/nar/gkaa937

There are 6285 14_3_3 domains in 6269 proteins in SMART's nrdb database.

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B561

Cytochrome b-561 / ferric reductase transmembrane domain.
B561
SMART accession number:SM00665
Description: Cytochrome b-561 recycles ascorbate for the generation of norepinephrine by dopamine-beta-hydroxylase in the chromaffin vesicles of the adrenal gland. It is a transmembrane heme protein with the two heme groups being bound to conserved histidine residues. A cytochrome b-561 homologue, termed Dcytb, is an iron-regulated ferric reductase in the duodenal mucosa. Other homologues of these are also likely to be ferric reductases. SDR2 is proposed to be important in regulating the metabolism of iron in the onset of neurodegenerative disorders.
Interpro abstract (IPR006593):

Cytochromes b561 constitute a class of intrinsic membrane proteins containing two haem molecules that are involved in ascorbate (vitamin C) regeneration. They have been suggested to function as electron transporters, shuttling electrons across membranes from ascorbate to an acceptor molecule. The one-electron oxidation product of ascorbate, monodehydro-ascorbate (MDHA) has been shown to function as an electon acceptor for mammalian and plant cytochromes b561. The cytochrome b561-catalysed reduction of MDHA results in the regeneration of the fully reduced ascorbate molecule. Cytochromes b561 have been identified in a large number of phylogenetically distant species, but are absent in prokaryotes. Most species contain three or four cytochrome b561 paralogous proteins [ (PUBMED:12801412) ].

Members of the cytochrome b561 protein family are characterised by a number of structural features, likely to play an essential part in their function. They are highly hydrophobic proteins with six transmembrane helices (named TMH1 through TMH6), four conserved histidine residues, probably coordinating the two haem molecules, and predicted substrate-binding sites for ascorbate and MDHA [ (PUBMED:12801412) ]. The functionally relevant and structurally most conserved region in the cytochrome b561 family is the TMH2 to -5 4-helix core with an amino acid composition that is very well conserved in the inner surface and somewhat less conserved in the outer surface of the core. The two terminal helices (TMH1 and TMH6) are less conserved [ (PUBMED:11532994) (PUBMED:12768339) ].

The entry represents a conserved region containing six transmembrane helices, found in cytochrome b651 and homologous proteins including some ferric reductases.

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B_lectin

Bulb-type mannose-specific lectin
B_lectin
SMART accession number:SM00108
Description: -
Interpro abstract (IPR001480):

A bulb lectin super-family (Amaryllidaceae, Orchidaceae and Aliaceae) contains a ~115-residue-long domain whose overall three dimensional fold is very similar to that of [ (PUBMED:9132060) (PUBMED:7664110) ]:

  • Dictyostelium discoideum comitin, an actin binding protein
  • Curculigo latifolia curculin, a sweet tasting and taste-modifying protein

This domain generally binds mannose, but in at least one protein, curculin, it is apparently devoid of mannose-binding activity.

Each bulb-type lectin domain consists of three sequential beta-sheet subdomains (I, II, III) that are inter-related by pseudo three-fold symmetry. The three subdomains are flat four-stranded, antiparrallel beta-sheets. Together they form a 12-stranded beta-barrel in which the barrel axis coincides with the pseudo 3-fold axis.

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BAG

BAG domains, present in regulator of Hsp70 proteins
BAG
SMART accession number:SM00264
Description: BAG domains, present in Bcl-2-associated athanogene 1 and silencer of death domains
Interpro abstract (IPR003103):

BAG domains are present in Bcl-2-associated athanogene 1 and silencer of death domains. The BAG proteins are modulators of chaperone activity, they bind to HSP70/HSC70 proteins and promote substrate release. The proteins have anti-apoptotic activity and increase the anti-cell death function of BCL-2 induced by various stimuli. BAG-1 binds to the serine/threonine kinase Raf-1 or Hsc70/Hsp70 in a mutually exclusive interaction. BAG-1 promotes cell growth by binding to and stimulating Raf-1 activity. The binding of Hsp70 to BAG-1 diminishes Raf-1 signalling and inhibits subsequent events, such as DNA synthesis, as well as arrests the cell cycle. BAG-1 has been suggested to function as a molecular switch that encourages cells to proliferate in normal conditions but become quiescent under a stressful environment [ (PUBMED:12406544) ].

BAG-family proteins contain a single BAG domain, except for human BAG-5 which has four BAG repeats. The BAG domain is a conserved region located at the C terminus of the BAG-family proteins that binds the ATPase domain of Hsc70/Hsp70. The BAG domain is evolutionarily conserved, and BAG domain containing proteins have been described and/or proven in a variety of organisms including Mus musculus (Mouse), Xenopus spp., Drosophila spp., Bombyx mori (Silk moth), Caenorhabditis elegans, Saccharomyces cerevisiae (Baker's yeast), Schizosaccharomyces pombe (Fission yeast), and Arabidopsis thaliana (Mouse-ear cress).

The BAG domain has 110-124 amino acids and is comprised of three anti-parallel alpha-helices, each approximately 30-40 amino acids in length. The first and second helices interact with the serine/threonine kinase Raf-1 and the second and third helices are the sites of the BAG domain interaction with the ATPase domain of Hsc70/Hsp70. Binding of the BAG domain to the ATPase domain is mediated by both electrostatic and hydrophobic interactions in BAG-1 and is energy requiring.

GO function:chaperone binding (GO:0051087)
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BH4

BH4 Bcl-2 homology region 4
BH4
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)
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BIR

Baculoviral inhibition of apoptosis protein repeat
BIR
SMART accession number:SM00238
Description: Domain found in inhibitor of apoptosis proteins (IAPs) and other proteins. Acts as a direct inhibitor of caspase enzymes.
Interpro abstract (IPR001370):

The 'baculovirus inhibitior of apoptosis protein repeat' (BIR) [ (PUBMED:8139034) (PUBMED:8552191) ] is a domain of about 70 residues arranged in tandem repeats separated by a variable length linker, that seems to confer cell death-preventing activity. It is found in proteins belonging to the IAP (inhibitor of apoptosis proteins) family. The critical motifs required for anti-apoptotic activity of IAP proteins are the BIRs. All IAP proteins contain from one to three BIRs, and all known interactions between IAPs and other proteins are mediated by one or more BIRs [ (PUBMED:10404221) ]. In higher eukaryotes, BIR domains inhibit apoptosis by acting as direct inhibitors of the caspase family of protease enzymes. Proteins with BIR domains are considered peptidase inhibitors in family I32. In yeast, BIR domains are involved in regulating cytokinesis. This novel fold is stabilized by zinc tetrahedrally coordinated by one histidine and three cysteine residues and resembles a classical zinc finger [ (PUBMED:8445726) ].

The BIR domain has a fold that is stabilised by zinc tetrahedrally coordinated by one histidine and three cysteine residues. The structure consists of three short alpha-helices and turns with the zinc packed in an unusually hydrophobic environment created by residues that are highly conserved among all BIRs. A subclass of repeats, comprising those at the C terminus of a series of BIR repeats from IAP proteins bearing RING finger domains, are likely to contain a C-terminal region that form an alpha-helix [ (PUBMED:10404221) ].

Proteins that are known to contain this domain include:

  • Baculoviruses apoptosis inhibitors (IAPs).
  • Mammalian apoptosis inhibitors 1 and 2 (IAP1 and IAP2; BIRC-2 and BIRC-3; MEROPS identifiers I32.002 and I32.003, respectively).
  • Mammalian X-linked inhibitor of apoptosis protein (X-linked IAP; MEROPS identifier I32.004).
  • Chicken IAP (ITA).
  • Human neuronal apoptosis inhibitory protein (NAIP, BIRC-1; MEROPS identifier I32.001).
  • Drosophila apoptosis inhibitors 1 and 2 (Iap1 and Iap2; MEROPS identifiers I32.009 and I32.011, respectively)).
  • African Swine Fever Virus (ASFV) protein p27.
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BTK

Bruton's tyrosine kinase Cys-rich motif
BTK
SMART accession number:SM00107
Description: Zinc-binding motif containing conserved cysteines and a histidine. Always found C-terminal to PH domains (but not all PH domains are followed by BTK motifs). The crystal structure shows this motif packs against the PH domain. The PH+Btk module pair has been called the Tec homology (TH) region.
Interpro abstract (IPR001562):

The Btk-type zinc finger or Btk motif (BM) is a conserved zinc-binding motif containing conserved cysteines and a histidine that is present in certain eukaryotic signalling proteins. The motif is named after Bruton's tyrosine kinase (Btk), an enzyme which is essential for B cell maturation in humans and mice [ (PUBMED:8070576) (PUBMED:15661031) ]. Btk is a member of the Tec family of protein tyrosine kinases (PTK). These kinases contain a conserved Tec homology (TH) domain between the N-terminal pleckstrin homology (PH) domain ( IPR001849 ) and the Src homology 3 (SH3) domain ( IPR001452 ). The N-terminal of the TH domain is highly conserved and known as the Btf motif, while the C-terminal region of the TH domain contains a proline-rich region (PRR). The Btk motif contains a conserved His and three Cys residues that form a zinc finger (although these differ from known zinc finger topologies), while PRRs are commonly involved in protein-protein interactions, including interactions with G proteins [ (PUBMED:9280283) (PUBMED:9796816) ]. The TH domain may be of functional importance in various signalling pathways in different species [ (PUBMED:8070576) ]. A complete TH domain, containing both the Btk and PRR regions, has not been found outside the Tec family; however, the Btk motif on its own does occur in other proteins, usually C-terminal to a PH domain (note that although a Btk motif always occurs C-terminal to a PH domain, not all PH domains are followed by a Btk motif).

The crystal structures of Btk show that the Btk-type zinc finger has a globular core, formed by a long loop which is held together by a zinc ion, and that the Btk motif is packed against the PH domain [ (PUBMED:8070576) ]. The zinc-binding residues are a histidine and three cysteines, which are fully conserved in the Btk motif [ (PUBMED:9218782) ].

Proteins known to contain a Btk-type zinc finger include:

  • Mammalian Bruton's tyrosine kinase (Btk), a protein tyrosine kinase involved in modulation of diverse cellular processes. Mutations affecting Btk are the cause of X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency in mice.
  • Mammalian Tec, Bmx, and Itk proteins, which are tyrosine protein kinases of the Tec subfamily.
  • Drosophila tyrosine-protein kinase Btk29A, which is required for the development of proper ring canals and of male genitalia and required for adult survival.
  • Mammalian Ras GTPase-activating proteins (RasGAP), which regulate the activation of inactive GDP-bound Ras by converting GDP to GTP.
GO process:intracellular signal transduction (GO:0035556)
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C1

Protein kinase C conserved region 1 (C1) domains (Cysteine-rich domains)
C1
SMART accession number:SM00109
Description: Some bind phorbol esters and diacylglycerol. Some bind RasGTP. Zinc-binding domains.
Interpro abstract (IPR002219):

Diacylglycerol (DAG) is an important second messenger. Phorbol esters (PE) are analogues of DAG and potent tumour promoters that cause a variety of physiological changes when administered to both cells and tissues. DAG activates a family of serine/threonine protein kinases, collectively known as protein kinase C (PKC) [ (PUBMED:1396661) ]. Phorbol esters can directly stimulate PKC. The N-terminal region of PKC, known as C1, has been shown [ (PUBMED:2500657) ] to bind PE and DAG in a phospholipid and zinc-dependent fashion. The C1 region contains one or two copies (depending on the isozyme of PKC) of a cysteine-rich domain, which is about 50 amino-acid residues long, and which is essential for DAG/PE-binding. The DAG/PE-binding domain binds two zinc ions; the ligands of these metal ions are probably the six cysteines and two histidines that are conserved in this domain.

GO process:intracellular signal transduction (GO:0035556)
Family alignment:
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