Messenger RNP

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Messenger RNP (messenger ribonucleoprotein) is mRNA with bound proteins. mRNA does not exist "naked" in vivo but is always bound by various proteins while being synthesized, spliced, exported, and translated in the cytoplasm. [1] [2]

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Messenger RNPs were first discovered in Alexander S. Spirin's laboratory in Moscow, Russia in 1964. The discovery was based in their study of fish embryo cytoplasm extracts, where they found these mRNPs. This finding was discovered after the mRNA of the fish embryo was centrifuged. The mRNA liquid separated into two parts, having the scientists question what is separate of the mRNA from the ribosomes. Spirin and his collaborators analyzed the mRNA against CsCl density gradients and discovered that parts of the mRNA were coated in proteins. The weight ratio of mRNPs was found to be 1:3, mRNA to protein. mRNPs were thus denoted as informosomes by the lab. [3]

There are three major informosomes found in mammalian cells: nuclear ribonucleoproteins, cytoplasmic informosomes, and polyribosomal messenger ribonucleoproteins. It was hypothesized by researchers that major roles of informosomes are to assist in mRNAs translocation from the nucleus to the cytoplasm, protect the mRNA against degradation, and help regulate protein formation. [4]

When mRNA is being synthesized by RNA polymerase, this nascent mRNA is already bound by RNA 5′ end 7-methyl-guanosine capping enzymes. Later, the pre-mRNA is bound by the spliceosome containing exon and intron definition complexes and proteins and RNA that catalyze the chemical reactions of splicing. Joan Steitz and Michael Lerner and collaborators showed that the small nuclear RNAs (snRNAs) are complexed into small nuclear Ribonuclear Proteins (snRNPs). [5] Christine Guthrie and collaborators showed that specific snRNAs encoded by single copy genes in yeast base pair with the pre-mRNA and direct each step in splicing. [2] The spliced mRNA is bound by another set of proteins which help in export from the nucleus to the cytoplasm. In vertebrates exon-exon junction are marked by exon junction complexes which in the cytosol can trigger nonsense mediated decay if the exon-exon junction is more than 50-55 nt downstream of the stop codon. [6]

Learning and memory

As described in a 2022 review, [7] long-term memory utilizes messenger RNP.

Rats with a new, strong long-term memory due to contextual fear conditioning have reduced expression of about 1,000 genes and increased expression of about 500 genes in the hippocampus 24 hours after training, thus exhibiting modified expression of 9.17% of the rat hippocampal genome. Reduced gene expressions were associated with methylations of those genes and hypomethylation was found for genes involved in synaptic transmission and neuronal differentiation. [8]

As described by Doyle and Kiebler, [9] “in the mature brain mRNA localization into dendrites of fully polarized neurons serves a distinct function. The presence of a specific set of transcripts and the entire translational machinery at dendritic spines suggests that local translation could be regulated in an activity-dependent manner.”

Neurodegenerative diseases

Neurodegenerative diseases in RNP granules are caused by genetic mutations. RNP granules store specific types of mRNAs under tight translational control while forming different types. Neuronal RNP granules that are connected to RNA binding proteins show signs of causing neurodevelopment, neurodegeneration or neuropsychiatric disorders. An example of one of these diseases would be spinal muscular atrophy (SMA) which affect the small nuclear ribonucleoprotein (snRNP). Although it is still unknown, increasing evidence ties neurodegeneration diseases with altered RNP granule homeostasis creating a concept of hypo and hyper-assembly diseases of RNPs. Hyper-assembly of RNP granule can be caused by two effects, one by mutations in the RNA binding protein while the other being an expansion of nucleotide repeats in the RNA. Another neurodegenerative disease amyotrophic lateral sclerosis (ALS) which is affected by the hyper assemble of RNP granule components. Even though neuronal cells are more susceptible to hypo- or hyper- assembly of RNP components there is still much unknown in terms of the full mutation process. [10]

Neuronal RNP granules assembly and regulation with flexible spatio-temporal that compartmentalize gene expression. The advanced technology that is present today helps uncover the behavior of neuronal RNP granules. It was recently discovered in a vitro study that the dynamic properties and structure of these RNP granules is fluid and generated through liquid-liquid phase separation. [10] Post-translational modification (PTM) of granule components have the means to modulate binding affinities that can do both condensation and dissolution.

See also

Related Research Articles

<span class="mw-page-title-main">RNA splicing</span> Process in molecular biology

RNA splicing is a process in molecular biology where a newly-made precursor messenger RNA (pre-mRNA) transcript is transformed into a mature messenger RNA (mRNA). It works by removing all the introns and splicing back together exons. For nuclear-encoded genes, splicing occurs in the nucleus either during or immediately after transcription. For those eukaryotic genes that contain introns, splicing is usually needed to create an mRNA molecule that can be translated into protein. For many eukaryotic introns, splicing occurs in a series of reactions which are catalyzed by the spliceosome, a complex of small nuclear ribonucleoproteins (snRNPs). There exist self-splicing introns, that is, ribozymes that can catalyze their own excision from their parent RNA molecule. The process of transcription, splicing and translation is called gene expression, the central dogma of molecular biology.

<span class="mw-page-title-main">Spliceosome</span> Molecular machine that removes intron RNA from the primary transcript

A spliceosome is a large ribonucleoprotein (RNP) complex found primarily within the nucleus of eukaryotic cells. The spliceosome is assembled from small nuclear RNAs (snRNA) and numerous proteins. Small nuclear RNA (snRNA) molecules bind to specific proteins to form a small nuclear ribonucleoprotein complex, which in turn combines with other snRNPs to form a large ribonucleoprotein complex called a spliceosome. The spliceosome removes introns from a transcribed pre-mRNA, a type of primary transcript. This process is generally referred to as splicing. An analogy is a film editor, who selectively cuts out irrelevant or incorrect material from the initial film and sends the cleaned-up version to the director for the final cut.

<span class="mw-page-title-main">SR protein</span>

SR proteins are a conserved family of proteins involved in RNA splicing. SR proteins are named because they contain a protein domain with long repeats of serine and arginine amino acid residues, whose standard abbreviations are "S" and "R" respectively. SR proteins are ~200-600 amino acids in length and composed of two domains, the RNA recognition motif (RRM) region and the RS domain. SR proteins are more commonly found in the nucleus than the cytoplasm, but several SR proteins are known to shuttle between the nucleus and the cytoplasm.

RNA-binding proteins are proteins that bind to the double or single stranded RNA in cells and participate in forming ribonucleoprotein complexes. RBPs contain various structural motifs, such as RNA recognition motif (RRM), dsRNA binding domain, zinc finger and others. They are cytoplasmic and nuclear proteins. However, since most mature RNA is exported from the nucleus relatively quickly, most RBPs in the nucleus exist as complexes of protein and pre-mRNA called heterogeneous ribonucleoprotein particles (hnRNPs). RBPs have crucial roles in various cellular processes such as: cellular function, transport and localization. They especially play a major role in post-transcriptional control of RNAs, such as: splicing, polyadenylation, mRNA stabilization, mRNA localization and translation. Eukaryotic cells express diverse RBPs with unique RNA-binding activity and protein–protein interaction. According to the Eukaryotic RBP Database (EuRBPDB), there are 2961 genes encoding RBPs in humans. During evolution, the diversity of RBPs greatly increased with the increase in the number of introns. Diversity enabled eukaryotic cells to utilize RNA exons in various arrangements, giving rise to a unique RNP (ribonucleoprotein) for each RNA. Although RBPs have a crucial role in post-transcriptional regulation in gene expression, relatively few RBPs have been studied systematically.It has now become clear that RNA–RBP interactions play important roles in many biological processes among organisms.

snRNPs, or small nuclear ribonucleoproteins, are RNA-protein complexes that combine with unmodified pre-mRNA and various other proteins to form a spliceosome, a large RNA-protein molecular complex upon which splicing of pre-mRNA occurs. The action of snRNPs is essential to the removal of introns from pre-mRNA, a critical aspect of post-transcriptional modification of RNA, occurring only in the nucleus of eukaryotic cells. Additionally, U7 snRNP is not involved in splicing at all, as U7 snRNP is responsible for processing the 3′ stem-loop of histone pre-mRNA.

Small nuclear RNA (snRNA) is a class of small RNA molecules that are found within the splicing speckles and Cajal bodies of the cell nucleus in eukaryotic cells. The length of an average snRNA is approximately 150 nucleotides. They are transcribed by either RNA polymerase II or RNA polymerase III. Their primary function is in the processing of pre-messenger RNA (hnRNA) in the nucleus. They have also been shown to aid in the regulation of transcription factors or RNA polymerase II, and maintaining the telomeres.

Gideon Dreyfuss is an American biochemist, the Isaac Norris Professor of Biochemistry and Biophysics at the University of Pennsylvania School of Medicine, and an investigator of the Howard Hughes Medical Institute. He was elected to the National Academy of Sciences in 2012.

Heterogeneous nuclear ribonucleoproteins (hnRNPs) are complexes of RNA and protein present in the cell nucleus during gene transcription and subsequent post-transcriptional modification of the newly synthesized RNA (pre-mRNA). The presence of the proteins bound to a pre-mRNA molecule serves as a signal that the pre-mRNA is not yet fully processed and therefore not ready for export to the cytoplasm. Since most mature RNA is exported from the nucleus relatively quickly, most RNA-binding protein in the nucleus exist as heterogeneous ribonucleoprotein particles. After splicing has occurred, the proteins remain bound to spliced introns and target them for degradation.

<span class="mw-page-title-main">LSm</span> Family of RNA-binding proteins

In molecular biology, LSm proteins are a family of RNA-binding proteins found in virtually every cellular organism. LSm is a contraction of 'like Sm', because the first identified members of the LSm protein family were the Sm proteins. LSm proteins are defined by a characteristic three-dimensional structure and their assembly into rings of six or seven individual LSm protein molecules, and play a large number of various roles in mRNA processing and regulation.

<span class="mw-page-title-main">U1 spliceosomal RNA</span>

U1 spliceosomal RNA is the small nuclear RNA (snRNA) component of U1 snRNP, an RNA-protein complex that combines with other snRNPs, unmodified pre-mRNA, and various other proteins to assemble a spliceosome, a large RNA-protein molecular complex upon which splicing of pre-mRNA occurs. Splicing, or the removal of introns, is a major aspect of post-transcriptional modification, and takes place only in the nucleus of eukaryotes.

<span class="mw-page-title-main">U4 spliceosomal RNA</span> Non-coding RNA component of the spliceosome

The U4 small nuclear Ribo-Nucleic Acid is a non-coding RNA component of the major or U2-dependent spliceosome – a eukaryotic molecular machine involved in the splicing of pre-messenger RNA (pre-mRNA). It forms a duplex with U6, and with each splicing round, it is displaced from the U6 snRNA in an ATP-dependent manner, allowing U6 to re-fold and create the active site for splicing catalysis. A recycling process involving protein Brr2 releases U4 from U6, while protein Prp24 re-anneals U4 and U6. The crystal structure of a 5′ stem-loop of U4 in complex with a binding protein has been solved.

<span class="mw-page-title-main">U7 small nuclear RNA</span>

The U7 small nuclear RNA is an RNA molecule and a component of the small nuclear ribonucleoprotein complex. The U7 snRNA is required for histone pre-mRNA processing.

<span class="mw-page-title-main">Survival of motor neuron</span> Protein in animal cells

Survival of motor neuron or survival motor neuron (SMN) is a protein that in humans is encoded by the SMN1 and SMN2 genes.

<span class="mw-page-title-main">HNRNPK</span> Human protein and coding gene

Heterogeneous nuclear ribonucleoprotein K is a protein that in humans is encoded by the HNRNPK gene. It is found in the cell nucleus that binds to pre-messenger RNA (mRNA) as a component of heterogeneous ribonucleoprotein particles. The simian homolog is known as protein H16. Both proteins bind to single-stranded DNA as well as to RNA and can stimulate the activity of RNA polymerase II, the protein responsible for most gene transcription. The relative affinities of the proteins for DNA and RNA vary with solution conditions and are inversely correlated, so that conditions promoting strong DNA binding result in weak RNA binding.

<span class="mw-page-title-main">HNRNPA2B1</span> Protein-coding gene in the species Homo sapiens

Heterogeneous nuclear ribonucleoproteins A2/B1 is a protein that in humans is encoded by the HNRNPA2B1 gene.

snRNP70 Protein-coding gene in the species Homo sapiens

snRNP70 also known as U1 small nuclear ribonucleoprotein 70 kDa is a protein that in humans is encoded by the SNRNP70 gene. snRNP70 is a small nuclear ribonucleoprotein that associates with U1 spliceosomal RNA, forming the U1snRNP a core component of the spliceosome. The U1-70K protein and other components of the spliceosome complex form detergent-insoluble aggregates in both sporadic and familial human cases of Alzheimer's disease. U1-70K co-localizes with Tau in neurofibrillary tangles in Alzheimer's disease.

<span class="mw-page-title-main">SYNCRIP</span> Protein-coding gene in the species Homo sapiens

Synaptotagmin-binding, cytoplasmic RNA-interacting protein (SYNCRIP), also known as heterogeneous nuclear ribonucleoprotein (hnRNP) Q or NS1-associated protein-1 (NSAP-1), is a protein that in humans is encoded by the SYNCRIP gene. As the name implies, SYNCRIP is localized predominantly in the cytoplasm. It is evolutionarily conserved across eukaryotes and participates in several cellular and disease pathways, especially in neuronal and muscular development. In humans, there are three isoforms, all of which are associated in vitro with pre-mRNAs, mRNA splicing intermediates, and mature mRNA-protein complexes, including mRNA turnover.

<span class="mw-page-title-main">HNRPF</span> Protein-coding gene in the species Homo sapiens

Heterogeneous nuclear ribonucleoprotein F is a protein that in humans is encoded by the HNRNPF gene.

<span class="mw-page-title-main">PTBP1</span> Protein-coding gene in the species Homo sapiens

Polypyrimidine tract-binding protein 1 is a protein that in humans is encoded by the PTBP1 gene.

<span class="mw-page-title-main">Exon junction complex</span> Protein complex assembled on mRNA

An exon junction complex (EJC) is a protein complex which forms on a pre-messenger RNA strand at the junction of two exons which have been joined together during RNA splicing. The EJC has major influences on translation, surveillance, localization of the spliced mRNA, and m6A methylation. It is first deposited onto mRNA during splicing and is then transported into the cytoplasm. There it plays a major role in post-transcriptional regulation of mRNA. It is believed that exon junction complexes provide a position-specific memory of the splicing event. The EJC consists of a stable heterotetramer core, which serves as a binding platform for other factors necessary for the mRNA pathway. The core of the EJC contains the protein eukaryotic initiation factor 4A-III bound to an adenosine triphosphate (ATP) analog, as well as the additional proteins Magoh and Y14. The binding of these proteins to nuclear speckled domains has been measured recently and it may be regulated by PI3K/AKT/mTOR signaling pathways. In order for the binding of the complex to the mRNA to occur, the eIF4AIII factor is inhibited, stopping the hydrolysis of ATP. This recognizes EJC as an ATP dependent complex. EJC also interacts with a large number of additional proteins; most notably SR proteins. These interactions are suggested to be important for mRNA compaction. The role of EJC in mRNA export is controversial.

References

  1. ↑ Hieronymus, Haley; Pamela A. Silver (2004-12-01). "A systems view of mRNP biology". Genes & Development. 18 (23): 2845–2860. doi: 10.1101/gad.1256904 . ISSN   0890-9369. PMID   15574591.
  2. 1 2 Bergkessel, Megan; Gwendolyn M. Wilmes; Christine Guthrie (2009-02-20). "SnapShot: Formation of mRNPs". Cell. 136 (4): 794–794.e1. doi: 10.1016/j.cell.2009.01.047 . ISSN   0092-8674. PMID   19239896.
  3. ↑ Spirin, Alexander (March 1979). "Messenger ribonucleoproteins (informosomes) and RNA-binding proteins". Molecular Biology Reports – Springer Journals . 5: 5 – via Springer Link.
  4. ↑ L. P. Ovchinnikov, T. N. Vlasik, S. P. Domogatsky, T. A. Seryakova, A. S. Spirin (1979). "Eukaryotic Translation Factors and RNA-Binding Proteins". Macromolecules in the Functioning Cell: 111–129 – via Springer Link.
  5. ↑ Lerner, Michael R.; Boyle, John A.; Mount, Stephen M.; Wolin, Sandra L.; Steitz, Joan A. (January 1980). "Are snRNPs involved in splicing?". Nature. 283 (5743): 220–224. Bibcode:1980Natur.283..220L. doi:10.1038/283220a0. ISSN   1476-4687. PMID   7350545. S2CID   4266714.
  6. ↑ Lykke-Andersen, Søren; Jensen, Torben Heick (2015-09-23). "Nonsense-mediated mRNA decay: an intricate machinery that shapes transcriptomes". Nature Reviews Molecular Cell Biology. 16 (11): 665–677. doi:10.1038/nrm4063. ISSN   1471-0080. PMID   26397022. S2CID   2693038.
  7. ↑ Bernstein C (2022). "DNA Methylation and Establishing Memory". Epigenet Insights. 15: 25168657211072499. doi:10.1177/25168657211072499. PMC   8793415 . PMID   35098021.
  8. ↑ Duke CG, Kennedy AJ, Gavin CF, Day JJ, Sweatt JD (July 2017). "Experience-dependent epigenomic reorganization in the hippocampus". Learn Mem. 24 (7): 278–288. doi:10.1101/lm.045112.117. PMC   5473107 . PMID   28620075.
  9. ↑ Doyle M, Kiebler MA (August 2011). "Mechanisms of dendritic mRNA transport and its role in synaptic tagging". EMBO J. 30 (17): 3540–52. doi:10.1038/emboj.2011.278. PMC   3181491 . PMID   21878995.
  10. 1 2 De Graeve, Fabienne; Besse, Florence (27 June 2018). "Neuronal RNP granules: from physiological to pathological assemblies". Biological Chemistry. 399 (7): 623–635. doi:10.1515/hsz-2018-0141. ISSN   1437-4315. PMID   29641413. S2CID   4792650.
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