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 [, ]. 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 () and the Src homology 3 (SH3) domain (). 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 [, ]. The TH domain may be of functional importance in various signalling pathways in different species []. 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 []. The zinc-binding residues are a histidine and three cysteines, which are fully conserved in the Btk motif []. 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.
Btk (Bruton tyrosine kinase) is a member of the Tec family, which is a group of nonreceptor tyrosine kinases containing Src homology protein interaction domains (SH3, SH2) N-terminal to the catalytic tyr kinase domain. Btk also contains an N-terminal pleckstrin homology (PH) domain, which binds the products of PI3K and allows membrane recruitment and activation, and the Tec homology (TH) domain with proline-rich and zinc-binding regions [].Btk is expressed in B-cells, and a variety of myeloid cells including mast cells, platelets, neutrophils, and dendrictic cells [, ]. It interacts with a variety of partners, from cytosolic proteins to nuclear transcription factors, suggesting a diversity of functions. Stimulation of a diverse array of cell surface receptors, including antigen engagement of the B-cell receptor (BCR), leads to PH-mediated membrane translocation of Btk and subsequent phosphorylation by Src kinase and activation []. Btk plays an important role in the life cycle of B-cells including their development, differentiation, proliferation, survival, and apoptosis []. Mutations in Btk cause the primary immunodeficiency disease, X-linked agammaglobulinaemia (XLA) in humans [, ]. This entry represents the SH3 domain of Btk.
Txk is a member of the Tec protein tyrosine kinase family. It plays a role in TCR signal transduction, T cell development, and selection which is analogous to the function of Itk. Txk has been shown to interact with IFN-gamma [, ]. Unlike most of the Tec family members Txk lacks a PH domain. Instead Txk has a unique region containing a palmitoylated cysteine string which has a similar membrane tethering function as the PH domain []. This entry includes the SH2 domain of Txk.The Tec protein tyrosine kinase family includes Tec,Btk, Itk, Bmx, and Txk. They contain an NH2-terminal pleckstrin homology (PH) domain (absent in Txk), a proline-rich region, Src-homology 3 (SH3) and SH2 domains, and a COOH-terminal PTK domain. The TH domain consists of a Zn2+-binding Btk motif and a proline-rich region. The Btk motif is found in Tec kinases, Ras GAP, and IGBP and crucial to the function of the PH domain. It is not present in Txk which is not surprising since it lacks a PH domain. The type 1 splice form of the Drosophila homologue also lacks both the PH domain and the Btk motif. The proline-rich regions are highly conserved for the most part with the exception of Bmx whose residues surrounding the PXXP motif are not conserved (TH-like) and Btk29A which is entirely unique with large numbers of glycine residues (TH-extended). Tec family members all lack a C-terminal tyrosine having an autoinhibitory function in its phosphorylated state [, ].
GAP1 (GTPase-activating protein 1) family members include RASA2 (GAP1m), RASAL (RASAL1), GAP1(IP4BP or RASA3), and CAPRI (RASA4). They all display Ras GAP activity. With the exception of RASA2, they all possess an arginine finger-dependent GAP activity on Rap1 [, ]. They contain N-terminal tandem C2 domain repeats, a centrally located Ras-GAP domain, and a PH (pleckstrin homology) domain containing a Btk motif [].RASAL, like Ca2+ -promoted Ras inactivator (CAPRI, or RASAL4), is a cytosolic protein that undergoes a rapid translocation to the plasma membrane in response to receptor-mediated elevation in the concentration of intracellular free Ca2+, a translocation that activates its ability to function as a RasGAP. However, unlike RASAL4, RASAL undergoes an oscillatory translocation to the plasma membrane that occurs in synchrony with repetitive Ca2+ spikes. Its tandem C2 domains bind phospholipids upon an elevation in the intracellular free Ca2+ concentration ([Ca2+]i) [].
GAP1 (GTPase-activating protein 1) family members include RASA2 (GAP1m), RASAL (RASAL1), GAP1(IP4BP or RASA3), and CAPRI (RASA4). They all display Ras GAP activity. With the exception of RASA2, they all possess an arginine finger-dependent GAP activity on Rap1 [, ]. They contain N-terminal tandem C2 domain repeats, a centrally located Ras-GAP domain, and a PH (pleckstrin homology) domain containing a Btk motif [].This entry represents the PH domain of Ras GTPase-activating protein 2 (RASA2, also known as GAP1m). The tandem C2 domains of RASA2, like those of GAP1IP4BP, do not contain the conserved C2 motif that is known to be required for calcium-dependent phospholipid binding. RASA2 is regulated by the binding of its PH domains to phophoinositides, PIP3 (phosphatidylinositol 3,4,5-trisphosphate) []. It suppresses RAS, enhancing the weak intrinsic GTPase activity of RAS proteins resulting in the inactive GDP-bound form of RAS, allowing control of cellular proliferation and differentiation []. RASA2 also binds to inositol 1,3,4,5-tetrakisphosphate (IP4) [].
GAP1 (GTPase-activating protein 1) family members include RASA2 (GAP1m), RASAL (RASAL1), GAP1(IP4BP or RASA3), and CAPRI (RASA4). They all display Ras GAP activity. With the exception of RASA2, they all possess an arginine finger-dependent GAP activity on Rap1 [, ]. They contain N-terminal tandem C2 domain repeats, a centrally located Ras-GAP domain, and a PH (pleckstrin homology) domain containing a Btk motif [].This entry represents the PH domain of Ras GTPase-activating protein 3 (RASA3, also known as GAP1 or IP4BP). The RASA3 PH domain binds to phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) and I(1,3,4,5)P4 []. Its C2 domains, like those of RASA2 (GAP1M), do not contain the C2 motif that is known to be required for calcium-dependent phospholipid binding [].
GAP1 (GTPase-activating protein 1) family members include RASA2 (GAP1m), RASAL (RASAL1), GAP1(IP4BP or RASA3), and CAPRI (RASA4). They all display Ras GAP activity. With the exception of RASA2, they all possess an arginine finger-dependent GAP activity on Rap1 [, ]. They contain N-terminal tandem C2 domain repeats, a centrally located Ras-GAP domain, and a PH (pleckstrin homology) domain containing a Btk motif [].This entry represents the PH domain of Ras GTPase-activating protein 4 (RASA4, also known as CAPRI). Both CAPRI and RASAL are calcium-activated RasGAPs that inactivate Ras at the plasma membrane. Its tandem C2 domains bind phospholipids upon an elevation in the intracellular free Ca2+ concentration ([Ca2+]i). CAPRI and RASAL differ in that CAPRI is an amplitude sensor while RASAL senses calcium oscillations [, ]. This difference between them resides not in their C2 domains, but in their PH domains leading to speculation that this might reflect an association with either phosphoinositides and/or proteins [].
GAP1 (GTPase-activating protein 1) family members include RASA2 (GAP1m), RASAL (RASAL1), GAP1(IP4BP or RASA3), and CAPRI (RASA4). They all display Ras GAP activity. With the exception of RASA2, they all possess an arginine finger-dependent GAP activity on Rap1 [, ]. They contain N-terminal tandem C2 domain repeats, a centrally located Ras-GAP domain, and a PH (pleckstrin homology) domain containing a Btk motif [].This entry represents the RasGAP domain of RASAL. RASAL, like Ca2+ -promoted Ras inactivator (CAPRI, or RASA4), is a cytosolic protein that undergoes a rapid translocation to the plasma membrane in response to receptor-mediated elevation in the concentration of intracellular free Ca2+, a translocation that activates its ability to function as a RasGAP. Its tandem C2 domains bind phospholipids upon an elevation in the intracellular free Ca2+ concentration ([Ca2+]i). CAPRI and RASAL differ in that CAPRI is an amplitude sensor while RASAL senses calcium oscillations [, ]. This difference between them resides not in their C2 domains, but in their PH domains leading to speculation that this might reflect an association with either phosphoinositides and/or proteins [].
