Descriptions

BTK is a non-receptor tyrosine kinase that belongs to the TEC family. The five members of the TEC family kinases (BTK, ITK, TEC, TXK, and BMX) are expressed in various hematopoietic cell lineages and relay signals downstream of multiple immunological receptors. BTK has been most well studied in B cells in the context of B-cell receptor (BCR) signaling, but it also plays a role in macrophages, mast cells, and dendritic cells downstream of Fc receptors and Toll-like receptors (TLRs). Antigen binding to the BCR triggers the activation of a trio of tyrosine kinases: LYN, SYK, and BTK. Association of BTK with PIP3 and SLP-65 activates BTK, which phosphorylates and activates PLCγ2.
BTK autoinhibition involves intramolecular interactions that maintain the kinase in an inactive conformation. The regulatory domains involved in BTK autoinhibition include the SH3, SH2, SH2-kinase link, and PH domains. Specific interactions include the binding of the SH3 domain to the SH2-kinase linker, SH2-kinase linker interaction with the kinase domain, and the SH2 domain docking onto the C-lobe of the kinase domain. The PH domain also plays a role by interacting with the kinase domain.
Specifically, the intramolecular interaction between SH3 domain (residues Y223, W251, and Y268) and the SH2-kinase linker (residues P385 and T387) stabilizes the SH3 domain onto the distal side of the kinase domain (opposite the activation loop face). The salt bridge contact between SH2 (R307) and (D656) in the kinase domain stabilizes the SH2 domain on the distal side of the kinase domain C-lobe and mimics the SH2/C-terminal tail phosphotyrosine interaction of the SRC kinases. L390 in the SH2-kinase linker and W421 and Y461 in the kinase domain N-lobe form the hydrophobic stack. The PH domain residues involved in the autoinhibitory pose are Y42 and D43 while the structural elements in the kinase domain reported to mediate this interaction include the αC-helix, the activation loop (A-loop), the αE–αF loop, and the αG-helix.

Accessory elements