This entry describes describes the B, or beta, subunit of the bcr type of benzoyl-CoA reductase, a 4-subunit enzyme. Many aromatic compounds are metabolized by way of benzoyl-CoA.
Abr (active breakpoint cluster region-related protein) and Bcr (breakpoint cluster region protein) are homologous proteins containing a C-terminal domain with GTPase-activating protein (GAP) activity specific for Rac. They control multiple cellular functions of murine macrophages []. They contain several domains, including tandem DH-PH, C2 and GAP domains. Bcr has an extra N-terminal oligomerization domain []. Bcr has been shown to fused to Abl tyrosine kinase in leukemia. The fusion of Bcr to Abl deregulates the tyrosine kinase activity of Abl []. The N-terminal oligomerization domain is thought to be the most critical component that allows the formation of homo-tetramer Bcr/Abl complexes and deregulates the Abl tyrosine kinase [, ]. The GTPase-activating activity of Bcr has been shown to be regulated by transglutaminase 2 (TG2), a multifunctional protein that has been implicated in numerous pathologies including that of neurodegeneration and celiac disease [, ].Abr is a critical regulator of Rho and Cdc42 during the single cell wound healing [].
Lime is involved in BCR (B-cell antigen receptor)-mediated signaling in B-cells and TCR (T-cell antigen receptor)-mediated T-cell signaling in T-cells. It couples activation of these receptors and their associated kinases with distal intracellular events such as calcium mobilisation or MAPK activation through the recruitment of PLCG2, GRB2, GRAP2, and other signaling molecules [, ].
The drug resistance transporter Bcr/CflA proteins are predicted to have 12 membrane-spanning regions. Members with known activity include Bcr (bicyclomycin resistance protein) in Escherichia coli [], Flor (chloramphenicol and florfenicol resistance) in Salmonella typhimurium [], and CmlA (chloramphenicol resistance) found on the Pseudomonas plasmid R1033 [].
This entry represents the BTB and C-terminal Kelch domain found in KLHL42, which is a substrate-specific adaptor of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex required for mitotic progression and cytokinesis. The BCR(KLHL42) E3 ubiquitin ligase complex mediates the ubiquitination and subsequent degradation of KATNA1. KLHL42 is involved in microtubule dynamics throughout mitosis [].
This entry represents a group of BTB/POZ domain-containing proteins, such as BACURD1-3 from humans. They act as the substrate-specific adapters of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex, which mediates the ubiquitination of RhoA, leading to its degradation by the proteasome []. This entry also includes EAP3 from Arabidopsis. The BTB/POZ domain of EAP3 displays poor conservation of the residues required for CUL3 binding and is not likely to function as an E3 ligase adaptor [].
KLHL2, also called actin-binding protein Mayven, is a novel actin-binding protein predominantly expressed in the brain. It plays a role in the reorganisation of the actin cytoskeleton, and promotes growth of cell projections in oligodendrocyte precursors [, ]. KLHL2 is a component of a cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex that mediates the ubiquitination of target proteins, such as NPTXR, leading most often to their proteasomal degradation [, ]. It contains a BTB domain and kelch repeat domains, characteristics of a kelch family protein.This entry represents the BTB/POZ domain, which is a common protein-protein interaction motif of about 100 amino acids.
This entry represents the C-terminal BACK (BTB and C-terminal Kelch) domain of speckle-type POZ protein (SPOP, also known as HIB homologue 1 or Roadkill homologue 1). This domain contains a pair of α-helices which seem to be conserved among Cul3 adaptors [].SPOP is an adaptor protein that forms a complex with Cul3, cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex, and is involved in ubiquitination of BMI1, H2AFY, and the death-associated protein 6 (DAXX) []. The C-terminal BACK domain of SPOP, may be involved in oligomer formation and in recruiting Cul3 (together with the adjacent BTB domain), whereas the N-terminal MATH domain recruits substrates [, ].
STAP1 is a signal-transducing adaptor protein. It is composed of a Pleckstrin Homology (PH) and SH2 domains along with several tyrosine phosphorylation sites. STAP-1 is an orthologue of BRDG1 (also known as BCR downstream signaling 1). STAP1 protein functions as a docking protein acting downstream of Tec tyrosine kinase in B cell antigen receptor signaling. The protein is phosphorylated by Tec and participates in a positive feedback loop, increasing Tec activity []. STAP-1 has been shown to interact with STAT5 []. This entry represents the SH2 domain of STAP1.In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites [, , ].
DAPP1/Bam32 is an adaptor protein that plays important roles in B cell receptor signalling, T cell receptor signalling and antibody affinity maturation in germinal centres []. It contains a putative myristoylation site at its N terminus, followed by a SH2 domain, and a pleckstrin homology (PH) domain at its C terminus. It translocates to the plasma membrane of B-lymphoma cells upon BCR (B-cell receptor) cross-linking; this translocation is PI3K (phosphoinositide 3-kinase)-dependent and PH domain-mediated []. This entry represents the SH2 domain of DAPP1/Bam32. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites [, , , , , ].
This entry represents the oligomerisation domain of the breakpoint cluster region oncoprotein Bcr, and the Bcr/Abl (Abelson-leukemia-virus) fusion protein created by a reciprocal (9;22) fusion []. Brc displays serine/threonine protein kinase activity (), acting as a GTPase-activating protein for RAC1 and CDC42. Brc promotes the exchange of RAC or CDC42-bound GDP by GTP, thereby activating them []. The Bcr/Abl fusion protein loses some of the regulatory function of Bcr with regards to small Rho-like GTPases with negative consequences on cell motility, in particular on the capacity to adhere to endothelial cells [].The Bcr, Bcr/Abl oncoprotein oligomerisation domain consists of a short N-terminal helix (alpha-1), a flexible loop and a long C-terminal helix (alpha-2). Together these form an N-shaped structure, with the loop allowing the two helices to assume a parallel orientation. The monomeric domains associate into a dimer through the formation of an antiparallel coiled coil between the alpha-2 helices and domain swapping of two alpha-1 helices, where one alpha-1 helix swings back and packs against the alpha-2 helix from the second monomer. Two dimers then associate into a tetramer. The oligomerisation domain is essential for the oncogenicity of the Bcr-Abl protein [].
This entry represents the oligomerisation domain of the breakpoint cluster region oncoprotein Bcr, and the Bcr/Abl (Abelson-leukemia-virus) fusion protein created by a reciprocal (9;22) fusion []. Brc displays serine/threonine protein kinase activity (), acting as a GTPase-activating protein for RAC1 and CDC42. Brc promotes the exchange of RAC or CDC42-bound GDP by GTP, thereby activating them []. The Bcr/Abl fusion protein loses some of the regulatory function of Bcr with regards to small Rho-like GTPases with negative consequences on cell motility, in particular on the capacity to adhere to endothelial cells [].The Bcr, Bcr/Abl oncoprotein oligomerisation domain consists of a short N-terminal helix (alpha-1), a flexible loop and a long C-terminal helix (alpha-2). Together these form an N-shaped structure, with the loop allowing the two helices to assume a parallel orientation. The monomeric domains associate into a dimer through the formation of an antiparallel coiled coil between the alpha-2 helices and domain swapping of two alpha-1 helices, where one alpha-1 helix swings back and packs against the alpha-2 helix from the second monomer. Two dimers then associate into a tetramer. The oligomerisation domain is essential for the oncogenicity of the Bcr-Abl protein [].
Lyn is a member of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. Lyn is expressed in B lymphocytes and myeloid cells. It exhibits both positive and negative regulatory roles in B cell receptor (BCR) signaling. Lyn, as well as Fyn and Blk, promotes B cell activation by phosphorylating ITAMs (immunoreceptor tyr activation motifs) in CD19 and in Ig components of BCR []. It negatively regulates signaling by its unique ability to phosphorylate ITIMs (immunoreceptor tyr inhibition motifs) in cell surface receptors like CD22 and CD5 []. Lyn also plays an important role in G-CSF receptor signaling by phosphorylating a variety of adaptor molecules []. Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction [, ].
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Tyrosine-protein kinases can transfer a phosphate group from ATP to a tyrosine residue in a protein. These enzymes can be divided into two main groups []:Receptor tyrosine kinases (RTK), which are transmembrane proteins involved in signal transduction; they play key roles in growth, differentiation, metabolism, adhesion, motility, death and oncogenesis []. RTKs are composed of 3 domains: an extracellular domain (binds ligand), a transmembrane (TM) domain, and an intracellular catalytic domain (phosphorylates substrate). The TM domain plays an important role in the dimerisation process necessary for signal transduction []. Cytoplasmic / non-receptor tyrosine kinases, which act as regulatory proteins, playing key roles in cell differentiation, motility, proliferation, and survival. For example, the Src-family of protein-tyrosine kinases [].This entry represents the non-receptor tyrosine kinases SYK and ZAP-70 [, , ]:SYK is a positive effector of BCR-stimulated responses. It couples the B-cell antigen receptor (BCR) to the mobilisation of calcium ion, either through a phosphoinositide 3-kinase-dependent pathway (when not phosphorylated on tyrosines of the linker region), or through a phospholipase C-gamma-dependent pathway (when phosphorylated on Tyr-342 and Tyr-346). Therefore, the differential phosphorylation of Syk can determine the pathway by which BCR is coupled to the regulation of intracellular calcium ion [, ].ZAP70 plays a role in T-cell development and lymphocyte activation. It is essential for TCR-mediated IL-2 production. Isoform 1 of ZAP70 induces TCR-mediated signal transduction, isoform 2 does not [, ].
