B-cell linker
Encyclopedia
The B-cell linker protein is encoded by the BLNK gene
and is an adaptor protein
also known as SLP-65, BASH, and BCA. BLNK is expressed in B cell
s and macrophage
s and plays a large role in B cell receptor signalling, in a fashion analogous to the role its paralogue SLP-76
plays in 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 B cell receptor.
, 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.
motif followed by an "acidic" region, a proline-rich region, and a C-terminal 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.
with Grb2
, SH3KBP1
, CD79A
, MAP4K1
and Bruton's tyrosine kinase
.
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
and is an adaptor protein
Adaptor protein
Signal transducing adaptor proteins are proteins which are accessory to main proteins in a signal transduction pathway. These proteins tend to lack any intrinsic enzymatic activity themselves but instead mediate specific protein–protein interactions that drive the formation of protein complexes...
also known as SLP-65, BASH, and BCA. BLNK is expressed in B cell
B cell
B cells are lymphocytes that play a large role in the humoral immune response . The principal functions of B cells are to make antibodies against antigens, perform the role of antigen-presenting cells and eventually develop into memory B cells after activation by antigen interaction...
s and macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
s and plays a large role in B cell receptor signalling, in a fashion analogous to the role its paralogue SLP-76
Lymphocyte cytosolic protein 2
Lymphocyte cytosolic protein 2 , also known as LCP2 or SLP-76, is a gene that encodes a signal-transducing adaptor protein.-Interactions:...
plays in T cell receptor
T cell receptor
The T cell receptor or TCR is a molecule found on the surface of T lymphocytes that is responsible for recognizing antigens bound to major histocompatibility complex molecules...
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 B cell receptor.
Function
The function of BLNK was first illustrated in BLNK deficient DT40 cells, a chicken B-cell line, which exhibited an abrogated intracellular calcium mobilisation response and impaired activation of MAP kinases p38P38 mitogen-activated protein kinases
P38 mitogen-activated protein kinases are a class of mitogen-activated protein kinases that are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock, and are involved in cell differentiation and apoptosis....
, JNK
C-Jun N-terminal kinases
c-Jun N-terminal kinases , were originally identified as kinases that bind and phosphorylate c-Jun on Ser-63 and Ser-73 within its transcriptional activation domain. They belong to the mitogen-activated protein kinase family, and are responsive to stress stimuli, such as cytokines, ultraviolet...
, and to a lesser degree ERK
Extracellular signal-regulated kinases
In molecular biology, extracellular-signal-regulated kinases or classical MAP kinases are widely expressed protein kinase intracellular signalling molecules that are involved in functions including the regulation of meiosis, mitosis, and postmitotic functions in differentiated cells...
upon B-cell receptor (BCR) activation as compared to wild type DT40 cells. In knockout mice
Knockout mouse
A knockout mouse is a genetically engineered mouse in which researchers have inactivated, or "knocked out," an existing gene by replacing it or disrupting it with an artificial piece of DNA...
, 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 leucine zipperLeucine zipper
A leucine zipper, aka leucine scissors, is a common three-dimensional structural motif in proteins. These motifs are usually found as part of a DNA-binding domain in various transcription factors, and are therefore involved in regulating gene expression...
motif followed by an "acidic" region, a proline-rich region, and a C-terminal SH2 domain
SH2 domain
The SH2 domain is a structurally conserved protein domain contained within the Src oncoprotein and in many other intracellular signal-transducing proteins...
. 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
CD79A
CD79a molecule, immunoglobulin-associated alpha, also known as mb-1, is a human gene.The mb-1 gene codes for a phosphoprotein, designated CD79a CD79a molecule, immunoglobulin-associated alpha, also known as mb-1, is a human gene.The mb-1 gene codes for a phosphoprotein, designated CD79a CD79a...
, 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
PLCG2
1-phosphatidylinositol-4,5-bisphosphate phosphodiesterase gamma-2 is an enzyme that in humans is encoded by the PLCG2 gene.- Function :Enzymes of the phospholipase C family catalyze the hydrolysis of phospholipids to yield diacylglycerols and water-soluble phosphorylated derivatives of the lipid...
, Btk
Bruton's tyrosine kinase
Bruton's tyrosine kinase is a type of kinase enzyme implicated in the primary immunodeficiency disease X-linked agammaglobulinemia . Its exact mechanism of action remains unknown, but it plays a crucial role in B cell maturation as well as mast cell activation through the high-affinity IgE receptor...
, Vav
Vav (protein)
Vav is a family of proteins involved in cell signalling. They act as guanine nucleotide exchange factors for small G proteins of the Rho family. GEF activity is mediated via module of tandem DH-PH domains. Vav proteins also appear to exhibit GEF-independent functions.There are three members of...
, and Nck
NCK1
Cytoplasmic protein NCK1 is a protein that in humans is encoded by the NCK1 gene.-Interactions:NCK1 has been shown to interact with DNM1, EIF2B2, KHDRBS1, Lymphocyte cytosolic protein 2, EPH receptor B1, SOCS7, MINK1, MAP4K1, MAP4K4, Abl gene, WIPF1, RRAS, Wiskott-Aldrich syndrome protein,...
.. 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 interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with Grb2
Grb2
Growth factor receptor-bound protein 2 also known as Grb2 is an adaptor protein involved in signal transduction/cell communication. In humans, the GRB2 protein is encoded by the GRB2 gene....
, SH3KBP1
SH3KBP1
SH3 domain-containing kinase-binding protein 1 is an enzyme that in humans is encoded by the SH3KBP1 gene.-Interactions:SH3KBP1 has been shown to interact with B-cell linker, Grb2, SH3GLB2, SH3GL3, SH3GL2, BCAR1, Epidermal growth factor receptor, CBLB, Cbl gene, SOS1, CRK and PAK2.-Further reading:...
, CD79A
CD79A
CD79a molecule, immunoglobulin-associated alpha, also known as mb-1, is a human gene.The mb-1 gene codes for a phosphoprotein, designated CD79a CD79a molecule, immunoglobulin-associated alpha, also known as mb-1, is a human gene.The mb-1 gene codes for a phosphoprotein, designated CD79a CD79a...
, MAP4K1
MAP4K1
Mitogen-activated protein kinase kinase kinase kinase 1 is a protein kinase that in humans is encoded by the MAP4K1 gene.. It is also known as HPK1 .-Interactions:...
and Bruton's tyrosine kinase
Bruton's tyrosine kinase
Bruton's tyrosine kinase is a type of kinase enzyme implicated in the primary immunodeficiency disease X-linked agammaglobulinemia . Its exact mechanism of action remains unknown, but it plays a crucial role in B cell maturation as well as mast cell activation through the high-affinity IgE receptor...
.