SLP65/SLP76, Csk-interacting membrane protein, termed SCIMP, belongs to family of transmembrane adaptor proteins (TRAP) which do not directly associate with a receptor, such as LAT, NTAL,

LIME Lime commonly refers to: * Lime (fruit), a green citrus fruit * Lime (material), inorganic materials containing calcium, usually calcium oxide or calcium hydroxide * Lime (color), a color between yellow and green Lime may also refer to: Botany ...

LAX Los Angeles International Airport , commonly referred to as LAX (with each letter pronounced individually), is the primary international airport serving Los Angeles, California and its surrounding metropolitan area. LAX is located in the We ...

. SCIMP is expressed in

antigen-presenting cell An antigen-presenting cell (APC) or accessory cell is a cell that displays antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize these complexes using ...

s (APC), namely

B cell B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...

s, bone marrow-derived dendritic cells and macrophages.

Structure and interactions

Like other TRAPs, SCIMP has negligible extracellular domain and transmembrane domain followed by intracellular domain, containing several tyrosines and one proline-rich region (PRR). Upon phosphorylation, these tyrosines serve as docking domains for

SH2 domain The SH2 (Src Homology 2) domain is a structurally conserved protein domain contained within the Src oncoprotein and in many other intracellular signal-transducing proteins. SH2 domains allow proteins containing those domains to dock to phosph ...

s containing proteins. In a contrast to phospho-tyrosines, proline rich regions are generally less susceptible to post-translation modifications and they are rather targets of constitutive interactions with

SH3 domain The SRC Homology 3 Domain (or SH3 domain) is a small protein domain of about 60 amino acid residues. Initially, SH3 was described as a conserved sequence in the viral adaptor protein v-Crk. This domain is also present in the molecules of phosp ...

s containing proteins. It has been shown that SCIMP interact via SH2 domains with Csk kinase, negative regulator of

Src family kinase Src kinase family is a family of non-receptor tyrosine kinases that includes nine members: Src, Yes, Fyn, and Fgr, forming the SrcA subfamily, Lck, Hck, Blk, and Lyn in the SrcB subfamily, and Frk in its own subfamily. Frk has homologs ...

s, but also with Slp65/76 and Grb2 adaptors, which are key pro-signalling soluble adaptor proteins in lymphocyte signalling network. SCIMP is constitutively associated with Lyn kinase via SH3 domain.

Membrane localization

Some of TRAPs are palmitoylated in a border region between transmembrane and intracellular domain. The aliphatic chain of

Palmitic acid Palmitic acid (hexadecanoic acid in IUPAC nomenclature) is a fatty acid with a 16-carbon chain. It is the most common saturated fatty acid found in animals, plants and microorganisms.Gunstone, F. D., John L. Harwood, and Albert J. Dijkstra. The ...

is anchored to the membrane bilayer and thus influence protein targeting to membrane microdomains. SCIMP is also palmitoylated and is associated with tetraspanin-enriched mircrodomains (TEMs). TEMs, unlike

lipid raft The cell membrane, plasma membranes of cells contain combinations of glycosphingolipids, cholesterol and protein Receptor (biochemistry), receptors organised in glycolipoprotein lipid microdomains termed lipid rafts. Their existence in cellular mem ...

s, are based more on protein-protein interactions than lipid-lipid/lipid-protein interactions. One of the resident proteins in TEMs is

MHC class II molecule MHC Class II molecules are a class of major histocompatibility complex (MHC) molecules normally found only on professional antigen-presenting cells such as dendritic cells, mononuclear phagocytes, some endothelial cells, thymic epithelial cells, ...

. SCIMP is present in the

immunological synapse In immunology, an immunological synapse (or immune synapse) is the interface between an antigen-presenting cell or target cell and a lymphocyte such as a T/B cell or Natural Killer cell. The interface was originally named after the neuronal sy ...

during antigen presentation between a

T cell A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell ...

and an

(APC).

In vitro studies and putative function

SCIMP becomes strongly phosphorylated after MHC II stimulation. Studies performed with fusion protein

CD25 Interleukin-2 receptor alpha chain (also called CD25) is the human protein encoded by the ''IL2RA'' gene. The interleukin 2 (IL2) receptor alpha (IL2RA) and beta (IL2RB) chains, together with the common gamma chain (IL2RG), constitute the high-a ...

-SCIMP showed its ability to induce

calcium release Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to ...

and Erk phosphorylation upon anti-CD25 antibody treatment. The calcium release was even stronger in CD25-SCIMP mutant protein in binding side for Csk. Indicating

negative feedback loop Negative feedback (or balancing feedback) occurs when some function of the output of a system, process, or mechanism is fed back in a manner that tends to reduce the fluctuations in the output, whether caused by changes in the input or by othe ...

performed by Csk kinase. Fusion proteins are commonly used in order to study signalling ability of proteins with a small extracellular domain hidden for antibody in membrane

glycocalix The glycocalyx, also known as the pericellular matrix, is a glycoprotein and glycolipid covering that surrounds the cell membranes of bacteria, epithelial cells, and other cells. In 1970, Martinez-Palomo discovered the cell coating in animal cells ...

. However knock down of SCIMP didn´t influence calcium release after anti MHC II antibody treatment, but only decrease level of Erk phosphorylation in longer time point (10 min.)

References

{{Reflist Immunology Proteins