Tripartite motif-containing protein 5 also known as RING finger protein 88 is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

that in humans is encoded by the ''TRIM5''

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

. The alpha isoform of this protein, TRIM5α, is a

retrovirus A retrovirus is a type of virus that inserts a DNA copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell. Once inside the host cell's cytoplasm, the virus uses its own reverse transcriptase ...

restriction factor, which mediates a species-specific early block to retrovirus infection. TRIM5α is composed of 493

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

s which is found in the

cells Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery w ...

of most

primate Primates are a diverse order of mammals. They are divided into the strepsirrhines, which include the lemurs, galagos, and lorisids, and the haplorhines, which include the tarsiers and the simians (monkeys and apes, the latter including huma ...

s. TRIM5α is an intrinsic immune factor important in the innate immune defense against retroviruses, along with the

APOBEC image:Apobec.J.Steinfeld.D.png, 300px, upExample of a member of the APOBEC family, APOBEC-2. A cytidine deaminase from ''Homo sapiens''.; ; rendered usinPyMOL APOBEC ("apolipoprotein B mRNA editing enzyme, catalytic polypeptide") is a family o ...

family of proteins,

tetherin Tetherin, also known as bone marrow stromal antigen 2, is a lipid raft associated protein that in humans is encoded by the ''BST2'' gene. In addition, tetherin has been designated as CD317 (cluster of differentiation 317). This protein is consti ...

and

TRIM22 Tripartite motif-containing 22, also known as TRIM22, is a protein which in humans is encoded by the ''TRIM22'' gene. Function The protein encoded by this gene is a member of the tripartite motif (TRIM) family. The TRIM motif includes three z ...

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 The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...

PRY-SPRY or B30.2 domain in addition to the other domains.

Function and means of action

When a

enters the host cell

cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...

, the retroviral

capsid A capsid is the protein shell of a virus, enclosing its genetic material. It consists of several oligomeric (repeating) structural subunits made of protein called protomers. The observable 3-dimensional morphological subunits, which may or may ...

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

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

proteins, which causes the TRIM5α to smother the (not yet uncoated)

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

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 Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases. Proteasomes are part of a major mechanism by w ...

-dependent degradation. The TRIM5α, once formed into its highly regular reticulatory net recruits ubiquitin for this purpose, which, in turn engages the

. The involvement of other cellular proteins in the inhibition mediated by TRIM5α is suspected but as yet not demonstrated. However,

Cyclophilin Cyclophilins (CYPs) are a family of proteins named after their ability to bind to ciclosporin (cyclosporin A), an immunosuppressant which is usually used to suppress rejection after internal organ transplants. They are found in all domains of lif ...

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

sequence of the

C-terminal domain The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...

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 Pan troglodytes endogenous retrovirus-1 (PtERV1), or chimpanzee endogenous retrovirus-1 (CERV1), is a retrovirus that putatively infected chimpanzees about 4 million years ago, and may have been involved in the process of speciation, making the c ...

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 An epidemic (from Ancient Greek, Greek ἐπί ''epi'' "upon or above" and δῆμος ''demos'' "people") is the rapid spread of disease to a large number of patients among a given population within an area in a short period of time. Epidemics ...

, 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 macaque The rhesus macaque (''Macaca mulatta''), colloquially rhesus monkey, is a species of Old World monkey. There are between six and nine recognised subspecies that are split between two groups, the Chinese-derived and the Indian-derived. Generally b ...

s, a species of

Old World monkey Old World monkey is the common English name for a family of primates known taxonomically as the Cercopithecidae (). Twenty-four genera and 138 species are recognized, making it the largest primate family. Old World monkey genera include baboons ...

s, appeared to be almost completely resistant to HIV-1, the virus that causes

AIDS Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV), a retrovirus. Following initial infection an individual m ...

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 The murine leukemia viruses (MLVs or MuLVs) are retroviruses named for their ability to cause cancer in murine (mouse) hosts. Some MLVs may infect other vertebrates. MLVs include both exogenous and endogenous viruses. Replicating MLVs have a pos ...

(MLV) as well as equine infectious anemia virus (EIAV). Prior to the discovery of TRIM5α as an antiviral protein, the inhibition

phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...

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 Night monkeys, also known as owl monkeys or douroucoulis (), are nocturnal New World monkeys of the genus ''Aotus'', the only member of the family Aotidae (). The genus comprises eleven species which are found across Panama and much of South Ame ...

, a species of

New World monkey New World monkeys are the five families of primates that are found in the tropical regions of Mexico, Central and South America: Callitrichidae, Cebidae, Aotidae, Pitheciidae, and Atelidae. The five families are ranked together as the Ceboidea ( ...

, 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

External links

* * * * * {{PDBe-KB2, Q9C035, Tripartite motif-containing protein 5

Structure

Function and means of action

Clinical significance

Notes and references

External links

See also