ATP-binding cassette sub-family E member 1 (ABCE1) also known as RNase L inhibitor (RLI) is an
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
that in humans is encoded by the ABCE1
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 b ...
.
ABCE1 is an
ATPase that is a member of the
ATP-binding cassette (ABC) transporters superfamily and OABP
subfamily.
ABCE1 inhibits the action of
ribonuclease L
Ribonuclease L or RNase L (for ''latent''), known sometimes as ribonuclease 4 or 2'-5' oligoadenylate synthetase-dependent ribonuclease — is an interferon (IFN)-induced ribonuclease which, upon activation, destroys all RNA within the cell (bot ...
. Ribonuclease L normally binds to 2-5A (5'-phosphorylated 2',5'-linked oligoadenylates) and inhibits the interferon-regulated 2-5A/RNase L pathway, which is used by viruses. ABCE1 heterodimerize with ribonuclease L and prevents its interaction with 2-5A, antagonizing the anti-viral properties of ribonuclease L, and allow the virus to synthesize viral proteins. It has also been implicated to have an effect in
tumor cell
A neoplasm () is a type of abnormal and excessive growth of tissue (biology), tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tiss ...
proliferation and
antiapoptosis.
ABCE1 is an essential and highly
conserved 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, res ...
that is required for both
eukaryotic translation
Eukaryotic translation is the biological process by which messenger RNA is translated into proteins in eukaryotes. It consists of four phases: gene translation, elongation, termination, and recapping.
Initiation
Translation initiation is the pr ...
initiation as well as
ribosome biogenesis
Ribosome biogenesis is the process of making ribosomes. In prokaryotes, this process takes place in the cytoplasm with the transcription of many ribosome gene operons. In eukaryotes, it takes place both in the cytoplasm and in the nucleolus. I ...
. The most studied homologues are Rli1p in
yeast
Yeasts are eukaryotic, single-celled microorganisms classified as members of the fungus kingdom. The first yeast originated hundreds of millions of years ago, and at least 1,500 species are currently recognized. They are estimated to constit ...
and Pixie in ''
Drosophila
''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many speci ...
''.
Structure
RLI is a 68 kDa cytoplasmic protein found in most
eukaryota and
archae. Since the crystal structure for RLI has not yet been determined, all that is known has been inferred from protein sequencing. The protein sequences between species is very well conserved, for example Pixie and yeast Rli1p are 66% identical, and Rli1p and human RLI are 67% identical.
RLI belongs to the ABCE family of
ATP-binding cassette
The ATP-binding cassette transporters (ABC transporters) are a transport system superfamily that is one of the largest and possibly one of the oldest gene families. It is represented in all extant phyla, from prokaryotes to humans. ABC transpo ...
(ABC) proteins. ABC proteins typically also contain a transmembrane region, and utilize ATP to transport substrates across a membrane, however RLI is unique in that it is a soluble protein that contains ABC domains. RLI has two C-terminal ABC domains; upon binding ATP they form a characteristic "ATP-sandwich," with two ATP molecules sandwiched between the two dimerized ABC domains. Hydrolysis of ATP allows the dimer to dissociate in a fully reversible process. Incubation of the protein with a non-hydrolyzable ATP analogue or a mutation of the ABC domain causes a complete loss of protein function.
RLI also has a cysteine-rich N-terminal region that is predicted to tightly bind two
Fe-4Sclusters. Mutation of this region, or depletion of available
Fe/S clusters, renders the protein unable to function, and loss of cell viability, making RLI the only known essential cytoplasmic protein dependent on Fe/S cluster biosynthesis in the
mitochondria. The function of the Fe/S clusters is unknown, although it has been suggested that they regulate the ABC domains in response to a change in the redox environment, for example in the presence of reactive oxygen species.
Function
RLI and its homologues in yeast and ''Drosophila'' have two major identified functions: translation initiation and ribosome biogenesis. In addition, human RLI is a known inhibitor of RNAse L. This was the first activity identified and the source of its name (RNAse L Inhibitor).
Translation Initiation
Translation initiation is an essential process required for proper protein expression and cell viability. Rli1p has been found to co-purify with
eukaryotic initiation factors, specifically eIF2, eIF5, and eIF3, as well as the 40S subunit of the ribosome. These initiation factors must associate with the ribosome in stoichiometric proportions, while Rli1p is required in catalytic amounts. The following mechanism for the process has been proposed: One ABC domain binds the 40S subunit, while the other binds an initiation factor. Binding of ATP allows for dimerization, which subsequently brings the initiation factor and ribosomal subunit in close enough contact to associate. ATP hydrolysis releases the two substrates and allows the cycle to begin again. This model is similar to one that has been proposed for DNA repair enzymes with ABC domains, in which each domain binds either side of a broken piece of DNA, with hydrolysis allowing the pieces to be brought together and subsequently repaired.
Ribosome recycling
Recycling is essential for ribosomes to become usable again after translating an mRNA or stalling. In both eukaryotes and archaea, ABCE1 is responsible for splitting a ribosome that has been bound to
Pelota Pelota (Spanish for ''ball'') can refer to the popular and shortened names for a number of ball games:
* Basque pelota
* Chaza
* Jai alai
* Mesoamerican ballgame
* Palla
* Pelota mixteca
* Valencian pilota
* Frontenis
* Pétanque
Pétanqu ...
or its paralog
eRF1. The exact movements leading to the split is not well understood.
Ribosome biogenesis
RLI and its homologues are also thought to play a role in
ribosome biogenesis
Ribosome biogenesis is the process of making ribosomes. In prokaryotes, this process takes place in the cytoplasm with the transcription of many ribosome gene operons. In eukaryotes, it takes place both in the cytoplasm and in the nucleolus. I ...
, nuclear export, or both. They have been found in the nucleus associated with the 40S and 60S subunits, as well as Hcr1p, a protein required for
rRNA
Ribosomal ribonucleic acid (rRNA) is a type of non-coding RNA which is the primary component of ribosomes, essential to all cells. rRNA is a ribozyme which carries out protein synthesis in ribosomes. Ribosomal RNA is transcribed from ribosoma ...
processing. It has been shown that the Fe/S clusters are necessary for ribosome biogenesis and/or nuclear export, although the exact mechanism is unknown.
RNAse inhibitor
Human RLI was first identified because of its ability to inhibit RNAse L, which plays a crucial role in antiviral activity in mammals. This cannot account for the conservation of the protein in all other organisms, since only mammals have the RNAse L system. It has been suggested that RLI in lower eukaryotes functions by inhibiting RNAses involved in ribosomal biosynthesis, thereby regulating the process.
Role in mitochondria
The mitochondria's energetic and metabolic functions have been established to be non-essential for yeast cell viability. The only function that has been implicated in being necessary for survival is the biosynthesis of Fe/S clusters. RLI is the only known essential cytoplasmic Fe/S protein that is absolutely dependent on the mitochondrial Fe/S synthesis and export system for proper maturation. Rli1p is therefore a novel link between the mitochondria and ribosome function and biosynthesis, and therefore the viability of the cell.
References
External links
ABCE1at NCBI
AceView genes
ABCE1at
GeneCards
GeneCards is a database of human genes that provides genomic, proteomic, transcriptomic, genetic and functional information on all known and predicted human genes. It is being developed and maintained by the Crown Human Genome Center at the Wei ...
* UniProt
{{ABC transporters
Protein biosynthesis
ATP-binding cassette transporters