Tripartite motif-containing protein 32 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 ''TRIM32''
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 ...
.
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 motif (TRIM) family. The TRIM motif includes three
zinc-binding domains, a
RING
Ring may refer to:
* Ring (jewellery), a round band, usually made of metal, worn as ornamental jewelry
* To make a sound with a bell, and the sound made by a bell
:(hence) to initiate a telephone connection
Arts, entertainment and media Film and ...
, a B-box type 1 and a B-box type 2, and a
coiled-coil
A coiled coil is a structural motif in proteins in which 2–7
alpha helix, alpha-helices are coiled together like the strands of a rope. (Protein dimer, Dimers and Protein trimer, trimers are the most common types.) Many coiled coil-type protei ...
region.
Subcellular distribution
The protein localizes to
cytoplasmic bodies. The protein has also been localized to the
nucleus
Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to:
*Atomic nucleus, the very dense central region of an atom
*Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA
Nucle ...
, where it interacts with the activation domain of the
HIV-1
The subtypes of HIV include two major types, HIV type 1 (HIV-1) and HIV type 2 (HIV-2). HIV-1 is related to viruses found in chimpanzees and gorillas living in western Africa, while HIV-2 viruses are related to viruses found in the sooty mangabey, ...
Tat protein. The Tat protein activates transcription of HIV-1 genes.
Interactions
TRIM32 has been shown to
interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with:
*
actin
Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of over ...
,
*
ABI2
Abl interactor 2 also known as Abelson interactor 2 (Abi-2) is a protein that in humans is encoded by the ''ABI2'' gene.
Interactions
ABI2 has been shown to Protein-protein interaction, interact with Abl gene, ABL1, ADAM19, and TRIM32.
Referen ...
*
c-Myc
''Myc'' is a family of regulator genes and proto-oncogenes that code for transcription factors. The ''Myc'' family consists of three related human genes: ''c-myc'' (MYC), ''l-myc'' (MYCL), and ''n-myc'' (MYCN). ''c-myc'' (also sometimes referre ...
,
*
dysbindin
Dysbindin, short for dystrobrevin-binding protein 1, is a protein constituent of the dystrophin-associated protein complex (DPC) of skeletal muscle cells. It is also a part of BLOC-1, or biogenesis of lysosome-related organelles complex 1. Dysbind ...
,
and
*
piasy,
Function
Mechanism
Currently, TRIM32 is believed to employ two different mechanisms to affect molecular targets. First, it can act through its
N-terminal
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
RING finger as an E3
ubiquitin ligase
A ubiquitin ligase (also called an E3 ubiquitin ligase) is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin ...
, responsible for attaching ubiquitin molecules to lysine residues of target proteins, in order to mark them for
proteosome
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 whi ...
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
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 ...
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-dep ...
, which has been shown to activate
miRNA
MicroRNA (miRNA) are small, single-stranded, non-coding RNA molecules containing 21 to 23 nucleotides. Found in plants, animals and some viruses, miRNAs are involved in RNA silencing and post-transcriptional regulation of gene expression. miRN ...
s.
Development
Research has recently shown the importance of TRIM32 in the development of the mouse
neocortex
The neocortex, also called the neopallium, isocortex, or the six-layered cortex, is a set of layers of the mammalian cerebral cortex involved in higher-order brain functions such as sensory perception, cognition, generation of motor commands, sp ...
. 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.
Skeletal muscle
TRIM32 is expressed in
skeletal muscle
Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...
, where it interacts with myosin and may
ubiquitin
Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...
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.
Clinical significance
Mutation-associated diseases
Bardet–Biedl syndrome
Bardet–Biedl syndrome (BBS) is a ciliopathic human genetic disorder that produces many effects and affects many body systems. It is characterized by rod/cone dystrophy, polydactyly, central obesity, hypogonadism, and kidney dysfunction in som ...
(BBS): TRIM32 is one of 14
[
]
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 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
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...
activity through ubiquitination of Protein Inhibitor of Activated STAT Y (
Piasy).
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
Keratinocytes are the primary type of Cell (biology), cell found in the epidermis (skin), epidermis, the outermost layer of the skin. In humans, they constitute 90% of epidermal skin cells.
Basal cells in the stratum basale, basal layer (''str ...
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
Abl interactor 2 also known as Abelson interactor 2 (Abi-2) is a protein that in humans is encoded by the ''ABI2'' gene.
Interactions
ABI2 has been shown to Protein-protein interaction, interact with Abl gene, ABL1, ADAM19, and TRIM32.
Referen ...
), which is a
tumor suppressor
A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or red ...
and inhibitor of cell migration.
See also
*
tripartite motif family The tripartite motif family (TRIM) is a protein 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 infe ...
References
External links
GeneReviews/NIH/NCBI/UW entry on Bardet-Biedl Syndrome
Further reading
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{{Ciliary proteins