trim5alpha trim5alpha tripartite motif-containing protein 5 also known as ring finger protein 88 is a protein that in humans is encoded by the trim5 gene. the alpha isoform of this protein, trim5α, is a retrovirus restriction factor, which mediates a species-specific early block to retrovirus infection. trim5available structurespdbortholog search: pdbe rcsb list of pdb id codes2ecv, 2yrgidentifiersaliasestrim5, rnf88, trim5alpha, tripartite motif containing 5external idsomim: 608487 mgi: 4821183 homologene: 75345 genecards: trim5 gene location (human)chr.chromosome 11 (human)band11p15.4start5,663,195 bpend5,938,619 bpgene location (mouse)chr.chromosome 7 (mouse)band7|7 e3start103,987,961 bpend104,002,569 bprna expression patternbgeehumanmouse (ortholog)top expressed insural nervegerminal epitheliumpalpebral conjunctivastromal cell of endometriumbody of pancreasseminal vesiculamonocytevisceral pleurabloodascending aortatop expressed inthymusfemale urethraduodenumbone marrowaortic valvespleenascending aortaesophagusjejunumleft lung lobemore reference expression databiogpsmore reference expression datagene ontologymolecular function protein-macromolecule adaptor activity protein homodimerization activity pattern recognition receptor activity zinc ion binding metal ion binding protein binding identical protein binding protein kinase binding transferase activity ubiquitin-protein transferase activity cellular component cytoplasm cytosol omegasome intracellular anatomical structure nucleus p-body biological process regulation of lipopolysaccharide-mediated signaling pathway interferon-gamma-mediated signaling pathway protein k63-linked ubiquitination immune system process protein trimerization positive regulation of dna-binding transcription factor activity regulation of protein localization autophagy positive regulation of nf-kappab transcription factor activity defense response to virus protein ubiquitination activation of innate immune response positive regulation of i-kappab kinase/nf-kappab signaling innate immune response viral process positive regulation of mapk cascade pattern recognition receptor signaling pathway negative regulation of viral entry into host cell sources:amigo / quickgoorthologsspecieshumanmouseentrez85363319236ensemblensg00000132256ensmusg00000057143uniprotq9c035d3z3l3refseq (mrna)nm_033034nm_033092nm_033093nm_001146007nm_175677refseq (protein)np_149023np_149083np_149084np_001139479np_783608location (ucsc)chr 11: 5.66 – 5.94 mbchr 7: 103.99 – 104 mbpubmed searchwikidataview/edit humanview/edit mouse trim5α is composed of 493 amino acids which is found in the cells of most primates. trim5α is an intrinsic immune factor important in the innate immune defense against retroviruses, along with the apobec family of proteins, tetherin and trim22. structure trim5α belongs to the trim protein family (trim stands for tripartite motif); this family was first identified by reddy in 1992 as a set of proteins which contain a ring type zinc finger domain, a b-box zinc binding domain, followed by a coiled-coil region. trim5α bears the c-terminal pry-spry or b30.2 domain in addition to the other domains. function and means of action when a retrovirus enters the host cell cytosol, the retroviral capsid was previously believed to undergo uncoating, though this (the complete uncoating theory) is now doubted; rather the true picture is thought to be that capsid uncoating does indeed take place in the cytosol but that it is a process which takes place progressively as the capsid gets closer and closer to the nucleus, though the uncoating process usually, but not always, completes in the nucleus. further, the viral genome in the capsid is reverse transcribed inside the viral capsid to enable the production of daughter virions. trim5α is present in the cytosol. it recognizes motifs within viral capsid proteins, which causes the trim5α to smother the (not yet uncoated) capsid in a reticulatory way so as to form a repeating regular hexagonal net, two sides of each hexagon being made up of two spokes of a three-way hub and spoke trimer and consequently to interfere with the viral capsid uncoating process, thereby preventing (1) transport of the viral genome to the host cell nucleus and (2) successful reverse transcription. the exact mechanism of action has not been shown conclusively, but capsid protein from restricted viruses (that is viruses which are the subject of trim5α intervention) is removed by proteasome-dependent degradation. the trim5α, once formed into its highly regular reticulatory net recruits ubiquitin for this purpose, which, in turn engages the proteasome. the involvement of other cellular proteins in the inhibition mediated by trim5α is suspected but as yet not demonstrated. however, cyclophilin a is important for the inhibition of hiv-1 by trim5α in old world monkey species. the "specificity" of restriction, that is, whether a given retrovirus can be targeted by trim5α, is entirely determined by the amino acid sequence of the c-terminal domain of the protein, called the b30.2/pry-spry domain. amino acid 332, which occurs within this domain, seems to play a critical role in determining the specificity of retrovirus restriction. trim5α may have played a critical role in the human immune defense system about 4 million years ago, when the retrovirus pterv1 was infecting the ancestors of modern chimpanzees. while no trace of pterv1 has yet been found in the human genome, about 130 traces of pterv1 dna have been found in the genome of modern chimpanzees. after recreating part of the pterv1 retrovirus, it was reported that trim5α prevents the virus from entering human cells in vitro. while this cellular defense mechanism may have been very useful 4 million years ago when facing a pterv1 epidemic, it has the side effect of leaving cells more susceptible to attack by the hiv-1 retrovirus. recently, doubt has been cast over these conclusions. by using a pterv1 capsid, which produces higher titer virus-like particles, perez-caballero et al. reported that pterv1 is not restricted by either human or chimpanzee trim5α. clinical significance rhesus macaques, a species of old world monkeys, appeared to be almost completely resistant to hiv-1, the virus that causes aids in humans. the rhesus macaques version of trim5α was very quick and had a high enough affinity to the incoming hiv capsule that it could bind and degrade it quickly so that the virus was neutralized. humans also have a trim5α, but it is not well enough tuned to mediate a sufficient response. however, the human version of trim5α can inhibit strains of the murine leukemia virus (mlv) as well as equine infectious anemia virus (eiav). prior to the discovery of trim5α as an antiviral protein, the inhibition phenotype had been described and coined ref1 (in human cells) and lv1 (in monkey cells). this terminology is now largely abandoned. a related protein, named trimcyp (or trim5-cypa), was isolated in the owl monkey, a species of new world monkey, and shown to potently inhibit infection by hiv-1. a similar protein has arisen independently in old world monkeys and has been identified in several species of macaque. it was recently described that interferon-α-mediated stimulation of the immunoproteasome enables human trim5α for effective capsid-dependent inhibition of hiv-1 dna synthesis and infection. notes and references grch38: ensembl release 89: ensg00000132256 - ensembl, may 2017 grcm38: ensembl release 89: ensmusg00000057143 - ensembl, may 2017 "human pubmed reference:". national center for biotechnology information, u.s. national library of medicine. 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