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Tripartite motif-containing protein 21, also known as E3 ubiquitin-protein ligase TRIM21, is a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
that in humans is encoded by the ''TRIM21''
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
. Alternatively spliced transcript variants for this gene have been described but the full-length nature of only one has been determined. It is expressed in most human tissues.


Structure

TRIM21 is a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains, a
RING finger domain In molecular biology, a RING (short for Really Interesting New Gene) finger domain is a protein structural domain of zinc finger type which contains a C3HC4 amino acid motif which binds two zinc cations (seven cysteines and one histidine arrang ...
, a B-box type 1 and a B-box type 2
zinc finger A zinc finger is a small protein structural motif that is characterized by the coordination of one or more zinc ions (Zn2+) which stabilizes the fold. The term ''zinc finger'' was originally coined to describe the finger-like appearance of a ...
, and a coiled coil region.


Function

TRIM21 is an intracellular antibody effector in the
intracellular antibody-mediated proteolysis Intracellular antibody-mediated degradation (IAMD) is a neutralization mechanism of intracellular antibody-mediated immunity whereby an effector protein, TRIM21, directs antibody bound virus, virions to the proteasome where they are degraded. As yet ...
pathway. It recognizes Fc domain and binds to immunoglobulin G, immunoglobulin A and
immunoglobulin M Immunoglobulin M (IgM) is the largest of several isotypes of antibodies (also known as immunoglobulin) that are produced by vertebrates. IgM is the first antibody to appear in the response to initial exposure to an antigen; causing it to also ...
on antibody marked non-enveloped virions which have infected the cell. Either by autoubiquitination or by ubiquitination of a cofactor, it is then responsible for directing the virions to the
proteasome Proteasomes are essential protein complexes responsible for the degradation of proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases. Proteasomes are found inside all e ...
. TRIM21 itself is not degraded in the proteasome unlike both the viral capsid and the bound antibody. TRIM21 is part of the RoSSA ribonucleoprotein, which includes a single polypeptide and one of four small RNA molecules. The RoSSA particle localizes to both the cytoplasm and the nucleus.


Clinical significance

RoSSA interacts with autoantigens in patients with Sjögren's syndrome and
systemic lupus erythematosus Lupus, formally called systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Common ...
. In addition, the inability for lupus-prone macrophages to degrade immune complexes in the lysosome results in the leakage of autoantibodies into the cytosol that can bind to TRIM21 and enhance NF-κB signaling. TRIM21 can be used to knockout specific proteins with their corresponding antibodies, a method known as Trim-Away. In this assay, TRIM21 and antibodies are delivered into cells through electroporation, and the targeted protein is degraded within a few minutes.


References


Further reading

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