Poly(A)-binding protein

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Poly(A) RNA binding protein PABP (PDB 1CVJ)

Poly(A)-binding protein (PAB or PABP)

polyadenylate polymerase by increasing its affinity towards RNA. Poly(A)-binding protein is also present during stages of mRNA metabolism including nonsense-mediated decay and nucleocytoplasmic trafficking. The poly(A)-binding protein may also protect the tail from degradation and regulate mRNA production. Without these two proteins in-tandem, then the poly(A) tail would not be added and the RNA would degrade quickly.[6]

Structure

RRM 1 and 2 connected by a short linker showing binding to the polyadenylate RNA.

Cytosolic poly-A binding protein (PABPC) is made up of four

NMR and X-ray crystallography studies have shown that RRMs are globular domains, each composed of 4 anti-parallel β sheets that are backed by 2 α-helices. The central two β-strands, connected by a short linker, of each RRM forms a trough-like surface that is thought to be responsible for binding to the poly(A) oligonucleotides. The polyadenylate RNA adopts an extended conformation running the length of the molecular trough. Adenine recognition is primarily mediated by contacts with conserved residues found in the RNP motifs of the two RRMs.[7] In vitro studies have shown the binding affinities to be on the order of 2-7nM, while affinity for poly(U), poly(G), and poly(C) were reportedly lower or undetectable in comparison. This shows that the poly(A)-binding protein is specific to poly(A) oligonucleotides and not others.[8]
Since the two central β-strands are used for poly(A) oligonucleotide binding, the other face of the protein is free for protein-protein interactions.

The PABC domain is approximately 75 amino acids and consists of 4 or 5 α-helices depending on the organism – human PABCs have 5, while

eukaryotic translation termination factor
(eRF3) and PABP interacting proteins 1 and 2 (PAIP 1, PAIP2).

The structure of human poly(A)-binding protein found in the nucleus (PABPN1) has yet to be well determined but it has been shown to contain a single RRM domain and an arginine rich carboxy terminal domain. They are thought to be structurally and functionally different from poly-A binding proteins found in the cytosol.

Expression and binding

The expression of mammalian poly(A)-binding protein is regulated at the translational level by a feed-back mechanism: the mRNA encoding PABP contains in its 5'

UTR
an A-rich sequence which binds poly(A)-binding protein. This leads to autoregulatory repression of translation of PABP.

The cytosolic isoform of eukaryotic poly(A)-binding protein binds to the initiation factor

eRF3). The eRF3/PABP1 interaction may promote recycling of terminating ribosomes from the 3' to 5' end, facilitating multiple rounds of initiation on an mRNA. Alternatively, it may link translation to mRNA decay, as eRF3 appears to interfere with the ability of PABP1 to multimerise/form on poly(A), potentially leading to PABP1 dissociation, deadenylation and, ultimately, turnover.[9]

Rotavirus NSP3

Cellular vs rotavirus translation

NSP3 interacts with eIF4GI and evicts the poly(A) binding protein from eIF4F. NSP3A by taking the place of PABP on eIF4GI, is responsible for the shut-off of cellular protein synthesis.[10] Rotavirus mRNAs terminate a 3’ GACC motif that is recognized by the viral protein
NSP3. This is the location where NSP3 competes with poly(A)-binding protein for eIF4G binding.

Once rotavirus infection occurs viral GACC-tailed mRNAs are translated while the poly(A)-tailed mRNA is severely impaired. In infected cells, there have been high magnitudes of both translation induction (GACC-tailed mRNA) and reduction (poly(A)-tailed mRNA) both dependent on the rotavirus strain. These data suggest that NSP3 is a translational surrogate of the PABP-poly(A) complex; therefore, it cannot by itself be responsible for inhibiting the translation of host poly(A)-tailed mRNAs upon rotavirus infection.[11]

PABP-C1 evicted from eIF4G by NSP3 accumulates in the nucleus of rotavirus-infected cells. This eviction process requires rotavirus NSP3, eIF4G, and RoXaN. To better understand the interaction, modeling of the NSP3-RoXaN complex, demonstrates mutations in NSP3 interrupt this complex without compromising NSP3 interaction with eIF4G. The nuclear localization of PABP-C1 is dependent on the capacity of NSP3 to interact with eIF4G and also requires the interaction of NSP3 with a specific region in RoXaN, the leucine- and aspartic acid-rich (LD) domain. RoXaN is identified as a cellular partner of NSP3 involved in the nucleocytoplasmic localization of PABP-C1.[12]

Associated diseases

OPMD

Oculopharyngeal muscular dystrophy (OPMD) is a genetic condition that occurs in adulthood often after the age of 40. This disorder usually leads to weaker facial muscles oftentimes showing as progressive eyelid drooping, swallowing difficulties, and proximal limb muscle weakness such as weak leg and hip muscles. People with this disorder are often hindered to the point that they have to use a cane in order to walk.[13] OPMD has been reported in approximately 29 countries and the number affected varies widely by specific population. The disease can be inherited as an autosomal dominant or recessive trait.[14]

Mutations

mRNA precursors.[15]

Mutations in PABPN1 that cause this disorder, result when the protein has an extended polyalanine tract (12-17 alanines long vs. the expected amount of 10). The extra alanines cause PABPN1 to aggregate and form clumps within muscles because they are not able to be broken down. These clumps are believed to disrupt the normal function of

muscle cells which eventually lead to cell death. This progressive loss of muscle cells most likely causes the weakness in muscles seen in patients with OPMD. It is still not known why this disorder only affects certain muscles like the upper leg and hip. In recent studies on OPMD in Drosophila, it has been shown that the degeneration of muscles within those who are affected may not solely be due to the expanded polyalanine tract. It may actually be due to the RNA-binding domain and its function in binding.[16]

Studies

As of November 2015, significant effort has been dedicated to researching OPMD and potential treatment methods. Myoblast Transplantation has been suggested and is in fact in clinical trials in France. This is done by taking

myoblasts from a normal muscle cell and putting them into pharyngeal muscles and allowing them to develop to help form new muscle cells. There has also been testing of compounds, either existing or developed, to see if they might combat OPMD and its symptoms. Trehalose is a special form of sugar that has shown reduced aggregate formation and delayed pathology in the mouse model of OPMD. Doxycycline also played a similar role in delaying toxicity of OPMD in mouse models most likely due to stopping aggregate formation and reduced apoptosis. Many other compounds and methods are currently being researched and showing some success in clinical trials leading to optimism in curing this disease.[17]

Genes

Multiple human genes encode different protein isoforms and paralogs of PABP, including PABPN1, PABPC1, PABPC3, PABPC4, PABPC5.[18]

References

  1. PMID 15630022
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  2. ^ Poly(A)-Binding+Proteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
  3. PMID 5288383
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  4. PMID 4718742
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  5. ^ "UniProtKB - Q86U42 (PABP2_HUMAN)". uniprot.org. Retrieved 17 November 2015.
  6. ^ Voet D, Voet J. Biochemistry (4th ed.). Wiley. p. 1304.
  7. PMID 10499800
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  8. PMID 23424172
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  9. PMID 15355595
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  10. PMID 9755181
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  11. PMID 26063427
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  12. PMID 18799579
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  13. ^ "Oculopharyngeal muscular dystrophy". Genetics Home Reference. National Library of Medicine.
  14. ^ "Oculopharyngeal Muscular Dystrophy". National Organization for Rare Disorders.
  15. ^ Shoubridge C (2000). "Polyalanine Tract Disorders and Neurocognitive Phenotypes". Madame Curie Bioscience Database.
  16. PMID 16642034
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  17. ^ "Research and Outcomes". University of New Mexico, School of Medicine.
  18. ^ PABPC5. HUGO Gene Nomenclature Committee. Accessed 8 April 2020.
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