B-cell linker

The B-cell linker protein is encoded by the BLNK is_associated_with::gene and is an is_associated_with::adaptor protein also known as SLP-65, BASH, and BCA. BLNK is expressed in is_associated_with::B cells and is_associated_with::macrophages and plays a large role in is_associated_with::B cell receptor signalling, in a fashion analogous to the role its paralogue SLP-76 plays in is_associated_with::T cell receptor signalling. As it has no known intrinsic enzymatic activity, the function of BLNK is to temporally and spatially coordinate and regulate signalling effectors downstream of the is_associated_with::B cell receptor.

Function
The function of BLNK was first illustrated in BLNK deficient DT40 cells, a is_associated_with::chicken is_associated_with::B-cell line, which exhibited an abrogated intracellular calcium mobilisation response and impaired activation of MAP kinases p38, JNK, and to a lesser degree ERK upon B-cell receptor (BCR) activation as compared to wild type DT40 cells. In knockout mice, BLNK deficiency results in a partial block in B-cell development, and in humans BLNK deficiency results in a much more profound block in B-cell development.

Structure
BLNK consists of a N-terminal is_associated_with::leucine zipper motif followed by an "acidic" region, a proline-rich region, and a C-terminal is_associated_with::SH2 domain. The leucine zipper motif allows BLNK to localise to the plasma membrane, presumably by coiled-coil interactions with a membrane protein. This leucine zipper motif distinguishes BLNK from its paralogue SLP-76 which, although having an N-terminal heptad-like organisation of leucine and isoleucine residues, has not been experimentally shown to have this motif. Recruitment of BLNK to the plasma membrane is also achieved by binding of the SH2 domain of BLNK to a non-ITAM phospho-tyrosine on Igα, a part of the B cell receptor complex.

The acidic region of BLNK contains several inducibly phosphorylated tyrosine residues, at least five in humans, that mediate protein-protein interactions between BLNK and PLCγ2, Btk, Vav, and Nck. A more recent mass spectrometry study of BLNK in DT40 cells found that at least 41 unique serine, threonine, and tyrosine residues are phosphorylated on BLNK.

Interactions
B-cell linker has been shown to interact with is_associated_with::Grb2,  is_associated_with::SH3KBP1, is_associated_with::CD79A,  is_associated_with::MAP4K1 and is_associated_with::Bruton's tyrosine kinase.