TRIM32
Encyclopedia
Tripartite motif-containing protein 32 is a protein
that in humans is encoded by the TRIM32 gene
. Since its discovery in 1995, TRIM32 has been shown to be implicated in a number of diverse biological pathways.
(TRIM) family. The TRIM motif includes three zinc-binding
domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil
region.
, where it interacts with the activation domain of the HIV-1 Tat
protein. The Tat protein activates transcription of HIV-1 genes.
with:
, responsible for attaching ubiquitin molecules to lysine residues of target proteins, in order to mark them for proteosome degradation. Currently evidence suggests TRIM32 ubiquitinates multiple proteins including c-Myc, dysbindin, actin, piasy, and Abl-interactor2 (ABI2). The second mechanism by which TRIM32 is believed to operate involves binding of proteins to the C-terminal NHL repeat
, which has been shown to activate miRNAs.
. In the mouse neocortex, neural progenitor cells generate daughter cells which either differentiate into specific neurons or maintain the progenitor state of the mother cell. TRIM32 helps control the balance between differentiating and progenitor cells by localizing to a pole during progenitor cell division, and thus becoming concentrated in one of the two daughter cells. This asymmetric division of TRIM32 induces neuronal differentiation in daughter cells which contain high TRIM32 concentrations, while cells with low TRIM32 concentrations retain progenitor cell fate. Proposed theories on how TRIM32 induces differentiation involve the ubiquitination of the transcription factor c-Myc and the binding of Argonaute-1
(Ago-1). The binding of Ago-1 induces activity of miRNAs, particularly Let-7a
, which has been shown to play a role in regulating proliferation and neuronal differentiation.
ate actin (it has been shown to do so in vitro). No difference has been observed between wild-type and LHMD2H-mutated TRIM32 in terms of actin or myosin binding, however, and thus the mechanism which causes the muscular dystrophy, LGMD2H, is still unknown. Additionally, TRIM32 is known to ubiquitinate dysbindin, a protein associated with both skeletal muscles and neural tissue. The purpose and effects of the ubiquitination of dysbindin are as yet unclear.
Limb-girdle muscular dystrophy
type2H (LGMD2H): LGMD2H is caused by 4 mutations of TRIM32 in the C-terminal NHL domain: D487N (third NHL repeat), R394H (first NHL repeat), T520TfsX13 (fourth NHL repeat), and D588del (fifth NHL repeat).
). Piasy acts as an inhibitor of NF-κB, and NF-κB acts as an anti-apoptotic factor. Thus, when Piasy is present, NF-κB is inhibited, and keratinocyte
s undergo apoptosis when exposed to ultraviolet-B radiation or TNFα, preventing cancer formation. When TRIM32 is overexpressed, Piasy is degraded, allowing NF-κB to function, and thus when cells are exposed to ultraviolet-B radiation or TNFα, apoptosis does not occur, potentially allowing cancer formation.
TRIM32 additionally promotes cancer formation by ubiquitinating Abl-interactor 2 (Abi2
), which is a tumor suppressor
and inhibitor of cell migration.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the TRIM32 gene
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...
. Since its discovery in 1995, TRIM32 has been shown to be implicated in a number of diverse biological pathways.
Structure
The protein encoded by this gene is a member of the tripartite motifTripartite motif family
-Function:Many TRIM proteins are induced by interferons, which are important component of resistance to pathogens and several TRIM proteins are known to be required for the restriction of infection by lentiviruses...
(TRIM) family. The TRIM motif includes three zinc-binding
Zinc finger
Zinc fingers are small protein structural motifs that can coordinate one or more zinc ions to help stabilize their folds. They can be classified into several different structural families and typically function as interaction modules that bind DNA, RNA, proteins, or small molecules...
domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil
Coiled coil
A coiled coil is a structural motif in proteins, in which 2-7 alpha-helices are coiled together like the strands of a rope . Many coiled coil type proteins are involved in important biological functions such as the regulation of gene expression e.g. transcription factors...
region.
Subcellular distribution
The protein localizes to cytoplasmic bodies. The protein has also been localized to the nucleusCell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
, where it interacts with the activation domain of the HIV-1 Tat
Tat (HIV)
Tat is an HIV gene.Tat stands for "Trans-Activator of Transcription". Tat consists of between 86 and 101 amino acids depending on the subtype.-Function:...
protein. The Tat protein activates transcription of HIV-1 genes.
Interactions
TRIM32 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:
- actinActinActin is a globular, roughly 42-kDa moonlighting protein found in all eukaryotic cells where it may be present at concentrations of over 100 μM. It is also one of the most highly-conserved proteins, differing by no more than 20% in species as diverse as algae and humans...
, - ABI2ABI2Abl interactor 2 also known as Abelson interactor 2 is a protein that in humans is encoded by the ABI2 gene.-Interactions:ABI2 has been shown to interact with ABL1,ADAM19, and TRIM32.-Further reading:...
- c-MycMycMyc is a regulator gene that codes for a transcription factor. In the human genome, Myc is located on chromosome 8 and is believed to regulate expression of 15% of all genes through binding on Enhancer Box sequences and recruiting histone acetyltransferases...
, - dysbindinDysbindinDysbindin, short for dystrobrevin-binding protein 1, is a protein constituent of the dystrophin-associated protein complex of skeletal muscle cells. It is also a part of BLOC-1, or biogenesis of lysosome-related organelles complex 1. Dysbindin was discovered by the research group of Derek Blake...
, and - piasyPIAS4E3 SUMO-protein ligase PIAS4 also known as protein inhibitor of activated STAT protein 4 or protein inhibitor of activated STAT protein gamma is an enzyme that in humans is encoded by the PIAS4 gene.-Interactions:...
,
Mechanism
Currently, TRIM32 is believed to employ two different mechanisms to affect molecular targets. First, it can act through its N-terminal RING finger as an E3 ubiquitin ligaseUbiquitin ligase
A ubiquitin ligase is a protein that in combination with an E2 ubiquitin-conjugating enzyme causes the attachment of ubiquitin to a lysine on a target protein via an isopeptide bond; the E3 ubiquitin ligase targets specific protein substrates for degradation by the proteasome...
, responsible for attaching ubiquitin molecules to lysine residues of target proteins, in order to mark them for proteosome degradation. Currently evidence suggests TRIM32 ubiquitinates multiple proteins including c-Myc, dysbindin, actin, piasy, and Abl-interactor2 (ABI2). The second mechanism by which TRIM32 is believed to operate involves binding of proteins to the C-terminal NHL repeat
NHL repeat
The NHL repeat, named after NCL-1, HT2A and Lin-41, is an amino acid sequence found largely in a large number of eukaryotic and prokaryotic proteins. For example, the repeat is found in a variety of enzymes of the copper type II, ascorbate-dependent monooxygenase family which catalyse the...
, which has been shown to activate miRNAs.
Development
Research has recently shown the importance of TRIM32 in the development of the mouse neocortexNeocortex
The neocortex , also called the neopallium and isocortex , is a part of the brain of mammals. It is the outer layer of the cerebral hemispheres, and made up of six layers, labelled I to VI...
. In the mouse neocortex, neural progenitor cells generate daughter cells which either differentiate into specific neurons or maintain the progenitor state of the mother cell. TRIM32 helps control the balance between differentiating and progenitor cells by localizing to a pole during progenitor cell division, and thus becoming concentrated in one of the two daughter cells. This asymmetric division of TRIM32 induces neuronal differentiation in daughter cells which contain high TRIM32 concentrations, while cells with low TRIM32 concentrations retain progenitor cell fate. Proposed theories on how TRIM32 induces differentiation involve the ubiquitination of the transcription factor c-Myc and the binding of Argonaute-1
EIF2C1
Protein argonaute-1 is a protein that in humans is encoded by the EIF2C1 gene.-Further reading:...
(Ago-1). The binding of Ago-1 induces activity of miRNAs, particularly Let-7a
Let-7 microRNA precursor
The Let-7 microRNA precursor was identified from a study of developmental timing in C. elegans, and was later shown to be part of a much larger class of non-coding RNAs termed microRNAs. miR-98 microRNA precursor from human is a let-7 family member. Let-7 miRNAs have now been predicted or...
, which has been shown to play a role in regulating proliferation and neuronal differentiation.
Skeletal muscle
TRIM32 is expressed in skeletal muscle, where it interacts with myocin and may ubiquitinUbiquitin
Ubiquitin is a small regulatory protein that has been found in almost all tissues of eukaryotic organisms. Among other functions, it directs protein recycling.Ubiquitin can be attached to proteins and label them for destruction...
ate actin (it has been shown to do so in vitro). No difference has been observed between wild-type and LHMD2H-mutated TRIM32 in terms of actin or myosin binding, however, and thus the mechanism which causes the muscular dystrophy, LGMD2H, is still unknown. Additionally, TRIM32 is known to ubiquitinate dysbindin, a protein associated with both skeletal muscles and neural tissue. The purpose and effects of the ubiquitination of dysbindin are as yet unclear.
Mutation-associated diseases
Bardet–Biedl syndrome (BBS): TRIM32 is one of 12 genes known to be linked with BBS. Specifically a mutation (P130S) in the B-box of TRIM32 gives rise to BBS.Limb-girdle muscular dystrophy
Limb-girdle muscular dystrophy
Limb-girdle muscular dystrophy or Erb's muscular dystrophy is an autosomal class of muscular dystrophy that is similar but distinct from Duchenne muscular dystrophy and Becker's muscular dystrophy...
type2H (LGMD2H): LGMD2H is caused by 4 mutations of TRIM32 in the C-terminal NHL domain: D487N (third NHL repeat), R394H (first NHL repeat), T520TfsX13 (fourth NHL repeat), and D588del (fifth NHL repeat).
Cancer
TRIM32 is overexpressed in skin cancer cells. It is thought that TRIM32 regulates NF-κB activity through ubiquitination of Protein Inhibitor of Activated STAT Y (PiasyPIAS4
E3 SUMO-protein ligase PIAS4 also known as protein inhibitor of activated STAT protein 4 or protein inhibitor of activated STAT protein gamma is an enzyme that in humans is encoded by the PIAS4 gene.-Interactions:...
). Piasy acts as an inhibitor of NF-κB, and NF-κB acts as an anti-apoptotic factor. Thus, when Piasy is present, NF-κB is inhibited, and keratinocyte
Keratinocyte
Keratinocytes are the predominant cell type in the epidermis, the outermost layer of the human skin, constituting 95% of the cells found there. Those keratinocytes found in the basal layer of the skin are sometimes referred to as "basal cells" or "basal keratinocytes"...
s undergo apoptosis when exposed to ultraviolet-B radiation or TNFα, preventing cancer formation. When TRIM32 is overexpressed, Piasy is degraded, allowing NF-κB to function, and thus when cells are exposed to ultraviolet-B radiation or TNFα, apoptosis does not occur, potentially allowing cancer formation.
TRIM32 additionally promotes cancer formation by ubiquitinating Abl-interactor 2 (Abi2
ABI2
Abl interactor 2 also known as Abelson interactor 2 is a protein that in humans is encoded by the ABI2 gene.-Interactions:ABI2 has been shown to interact with ABL1,ADAM19, and TRIM32.-Further reading:...
), which is a tumor suppressor
Tumor suppressor gene
A tumor suppressor gene, or anti-oncogene, is a gene that protects a cell from one step on the path to cancer. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes.-Two-hit hypothesis:Unlike...
and inhibitor of cell migration.