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[[Image:Poly(A)-binding protein.png|thumb|Poly(A) RNA Binding Protein PABP, PDB 1CVJ]]
[[Image:Poly(A)-binding protein.png|thumb|Poly(A) RNA Binding Protein PABP, PDB 1CVJ]]
'''Poly(A)-binding protein''' ('''PAB''' or '''PABP''')<ref name="pmid15630022">{{cite journal |author=Kahvejian A, Svitkin YV, Sukarieh R, M'Boutchou MN, Sonenberg N |title=Mammalian poly(A)-binding protein is a eukaryotic translation initiation factor, which acts via multiple mechanisms |journal=Genes Dev. |volume=19 |issue=1 |pages=104–13 |date=January 2005 |pmid=15630022 |pmc=540229 |doi=10.1101/gad.1262905 |url=http://www.genesdev.org/cgi/pmidlookup?view=long&pmid=15630022}}</ref> is a [[RNA-binding protein]] which binds to the [[poly(A) tail]] of [[mRNA]].<ref>{{MeshName|Poly(A)-Binding+Proteins}}</ref> The poly(A) tail is located on the 3' end of mRNA and is 200-250 nucleotides long. The binding protein is also involved in [[Precursor mRNA|mRNA precursors]] by helping Polyadenylate polyermase add the Poly(A) nucleotide tail to the pre-mRNA before [[Translation (biology)|translation]].<ref>{{cite web|title=UniProtKB - Q86U42 (PABP2_HUMAN)|url=http://www.uniprot.org/uniprot/Q86U42|website=uniprot.org|accessdate=17 November 2015}}</ref> The nuclear [[isoforms|isoform]] selectively binds to around 50 nucleotides and stimulates the activity of [[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.<ref>{{cite book|last1=Voet|first1=Donald|last2=Voet|first2=Judith|title=Biochemistry|publisher=Wiley|page=1304|edition=4}}</ref>
'''Poly(A)-binding protein''' ('''PAB''' or '''PABP''')<ref name="pmid15630022">{{cite journal |author=Kahvejian A, Svitkin YV, Sukarieh R, M'Boutchou MN, Sonenberg N |title=Mammalian poly(A)-binding protein is a eukaryotic translation initiation factor, which acts via multiple mechanisms |journal=Genes Dev. |volume=19 |issue=1 |pages=104–13 |date=January 2005 |pmid=15630022 |pmc=540229 |doi=10.1101/gad.1262905 |url=http://www.genesdev.org/cgi/pmidlookup?view=long&pmid=15630022}}</ref> is a [[RNA-binding protein]] which binds to the [[poly(A) tail]] of [[mRNA]].<ref>{{MeshName|Poly(A)-Binding+Proteins}}</ref> The poly(A) tail is located on the 3' end of mRNA. The nuclear [[isoforms]] selectively binds to around 50 nucleotides and stimulates the activity of [[Polyadenylate polymerase]].

==Poly(A) Binding Protein Structure==
[[File:PABP Motifs.jpg|thumb|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 [[RNA recognition motif|RNA recognition motifs]] (RRMs) and a C-terminal region known as the PABC domain. RRM is the most common motifs for RNA recognition and is usually made up of 90-100 [[amino acids]]. Previous solution [[NMR]] and [[X-ray crystallography]] studies have shown that RRMs are [[protein domain|globular domains]], each composed of 4 anti-parallel [[beta sheet|β sheets]] that are backed by 2 [[alpha helix|α-helices]]. The central two β-strands, connected by a short linker, of each RRM forms a trough-like surface that’s thought to be responsible for binding to the poly(A) [[Oligonucleotide|oligonucleotides]]. The polyadenylate RNA adopts an extended conformation running the length of the molecular trough. [[Adenine]] recognition is primarily mediated by contacts with [[Conserved sequence|conserved residues]] found in the [[RNA recognition motif|RNP motifs]] of the two RRMs.<ref>{{cite journal|last1=Deo|first1=Rahul|title=Recognition of Polyadenylate RNA by the Poly(A)-Binding Protein|journal=Cell (Cambridge,Mass.)|date=Sep 1999|volume=98|page=835-845|pmid=10499800|url=http://www.ncbi.nlm.nih.gov/pubmed/10499800?dopt=Abstract}}</ref> 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.<ref>{{cite journal|last1=Goss|first1=DJ|last2=Kleiman|first2=FE|title=Poly(A) binding proteins: are they all created equal?|journal=Wiley Interdisciplinary Review. RNA.|date=2013|page=167-179|doi=10.1002/wrna|pmid=23424172|url=http://www.ncbi.nlm.nih.gov/pubmed/23424172}}</ref> 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 [[yeast]] has been observed to have 4. This domain does not contact RNA, and instead, it recognizes 15 residues sequences that are a part of the PABP interaction motif (PAM-2) found on such proteins as [[Eukaryotic release factors|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 [[Carboxylic acid|carboxy]] terminal domain. They are thought to be structurally and functionally different from Poly-A Binding Proteins found in the [[cytosol]].


==Expression and binding==
==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' [[Untranslated Region|UTR]] an A-rich sequence which binds Poly(A)-binding protein. This leads to autoregulatory repression of translation of PABP.
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' [[Untranslated Region|UTR]] an A-rich sequence which binds Poly(A)-binding protein. This leads to autoregulatory repression of translation of PABP.


The cytosolic isoform of eukaryotes' Poly(A) binding protein binds to the initiation factor [[eIF-4G]] via its C-terminal domain. EIF-4G is bound to [[eIF-4E]], another initiation factor bound to the [[5' cap]] on the 5' end of mRNA. This binding forms the characteristic loop structure of [[Eukaryotic translation|eukaryotic protein synthesis]]. Poly(A)-binding proteins in the cytosol compete for the eIF-4G binding sites. This interaction enhances both the affinity of eIF-4E for the cap structure and PABP1 for poly(A), effectively locking proteins onto both ends of the mRNA. As a result, this association may in part underlie the ability of PABP1 to promote small [[ribosome|ribosomal]] (40S) subunit recruitment, which is aided by the interaction between eIF-4G and [[Eukaryotic initiation factor|eIF3]]. Poly(A)-binding protein has also been shown to interact with a termination 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 (biology)|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, [[Polyadenylation|deadenylation]] and, ultimately, turnover.<ref>{{cite journal|last1=Gorgoni|first1=Barbara|last2=Gray|first2=Nicola|title=The roles of cytoplasmic poly(A)-binding proteins in regulating gene expression: A developmental perspective|journal=Briefing in Functional Genomics and Proteomics|date=Aug 2004|volume=3|issue=2|page=125-141|url=http://bfg.oxfordjournals.org/content/3/2/125.full.pdf}}</ref>
The cytosolic isoform of eukaryotes' Poly(A) binding protein binds to the initiation factor [[eIF-4G]] via its C-terminal domain. EIF-4G is bound to [[eIF-4E]], another initiation factor bound to the [[5' cap]] on the 5' end of mRNA. This binding forms the characteristic loop structure of eukaryotic protein synthesis. Poly(A)-binding protein interacting proteins in the cytosol compete for the eIF-4G binding sites. Poly(A)-binding protein has also been shown to interact with a termination factor ([[eRF3]])

==Rotavirus NSP3’s Involvement with Poly(A)-Binding Protein==


==Rotavirus NSP3==
[[Image:Rotavirus Translation.svg|thumb|Cellular vs Rotavirus Translation]]
[[Image:Rotavirus Translation.svg|thumb|Cellular vs Rotavirus Translation]]
[[Rotavirus]] [[RNA-binding protein]] [[NSP3(Rotavirus)|NSP3]] interacts with [[Eukaryotic initiation factor|eIF4GI]] and evicts the poly(A) binding protein from [[Eukaryotic initiation factor|eIF4F]]. And NSP3A, by taking the place of PABP on [[Eukaryotic initiation factor|eIF4GI]], is responsible for the shut-off of cellular protein synthesis.<ref name=pmid9755181>{{Cite journal |pmid=9755181 |doi=10.1093/emboj/17.19.5811 |year=1998 |last1=Piron |first1=M |last2=Vende |last3=Cohen |last4=Poncet |title=Rotavirus RNA-binding protein NSP3 interacts with eIF4GI and evicts the poly(A) binding protein from eIF4F |volume=17 |issue=19 |pages=5811–21 |journal=The EMBO Journal |format=Free full text |first2=P |first3=J |first4=D |pmc=1170909}}</ref>. 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.
[[Rotavirus]] [[RNA-binding protein]] [[NSP3(Rotavirus)|NSP3]] interacts with [[Eukaryotic initiation factor|eIF4GI]] and evicts the poly(A) binding protein from [[Eukaryotic initiation factor|eIF4F]]. And NSP3A, by taking the place of PABP on [[Eukaryotic initiation factor|eIF4GI]], is responsible for the shut-off of cellular protein synthesis.<ref name=pmid9755181>{{Cite journal |pmid=9755181 |doi=10.1093/emboj/17.19.5811 |year=1998 |last1=Piron |first1=M |last2=Vende |last3=Cohen |last4=Poncet |title=Rotavirus RNA-binding protein NSP3 interacts with eIF4GI and evicts the poly(A) binding protein from eIF4F |volume=17 |issue=19 |pages=5811–21 |journal=The EMBO Journal |format=Free full text |first2=P |first3=J |first4=D |pmc=1170909}}</ref>

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.<ref>{{cite journal|last1=Gratia|first1=M|title=Rotavirus NSP3 Is a Translational Surrogate of the Poly(A) Binding Protein-Poly(A) Complex.|journal=Journal of Virology|date=Sep 2015|page=8773-82|doi=10.1128/JVI.01402-15|pmid=26063427|url=http://www.ncbi.nlm.nih.gov/pubmed/26063427}}</ref>

PABP-C1 evicted from eIF4G by NSP3 accumulates in the nucleus of rotavirus-infected cells. This eviction process requires rotavirus NSP3, eIF4G, and [[Roxan (protein)|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 sequence|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.<ref>{{cite journal|last1=Harb|first1=Maya|title=Nuclear Localization of Cytoplasmic Poly(A)-Binding Protein upon Rotavirus Infection Involves the Interaction of NSP3 with eIF4G and RoXaN|journal=Journal of Virology|date=Nov 2008|volume=82|issue=22|page=11283-11293|doi=10.1128/JVI.00872-08|url=http://jvi.asm.org/content/82/22/11283.short}}</ref>

==Diseases associated with PABP==

===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 often times 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.<ref>{{cite web|title=Oculopharyngeal muscular dystrophy|url=http://ghr.nlm.nih.gov/condition/oculopharyngeal-muscular-dystrophy|website=Genetics Home Reference|publisher=National Library of Medicine}}</ref> 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 [[Dominance (genetics)|dominant]] or [[Dominance (genetics)|recessive]] trait.<ref>{{cite web|title=Oculopharyngeal Muscular Dystrophy|url=https://rarediseases.org/rare-diseases/oculopharyngeal-muscular-dystrophy/|website=National Organization for Rare Disorders}}</ref>

===Mutations===
[[Mutation|Mutations]] of Poly(A) Binding protein nuclear 1 (PABPN1) can cause OPMD (Oculopharyngeal Muscular Dystrophy). What makes the PABPN1 protein so different than all other genes with disease causing expanded [[Alanine|polyalanine]] tracts, is that it is not a [[transcription factor]]. Instead, PABPN1 is involved in the polyadenylation of [[Precursor mRNA|mRNA Precursors]].<ref>{{cite journal|last1=Shoubridge|first1=Cheryl|title=Polyalanine Tract Disorders and Neurocognitive Phenotypes|journal=Madame Curie Bioscience Database|date=2000|url=http://www.ncbi.nlm.nih.gov/books/NBK51932/}}</ref>

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 [[Myocyte|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 within [[drosophila]] flies, 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.<ref>{{cite journal|last1=Chartier|first1=Aymeric|title=A Drosophila model of oculopharyngeal muscular dystrophy reveals intrinsic toxicity of PABPN1|journal=The EMBO Journal|date=2006|volume=25|issue=10|page=2253-2262|doi=10.1038/sj.emboj.7601117|url=http://emboj.embopress.org/content/25/10/2253}}</ref>

===Gene Location===
The PABPN1 gene is located on the long (q) arm of [[chromosome]] 14 at position 11.2. More precisely, the PABPN1 gene is located from [[base pair]] 23,320,188 to base pair 23,326,185 on chromosome 14.<ref>{{cite web|title=PABPN1|url=http://ghr.nlm.nih.gov/gene/PABPN1|website=Genetics Home Reference|publisher=US National Library of Medicine}}</ref>


==Genes==
==Genes==

Revision as of 18:14, 17 November 2015

Poly(A) RNA Binding Protein PABP, PDB 1CVJ

Poly(A)-binding protein (PAB or PABP)[1] is a RNA-binding protein which binds to the poly(A) tail of mRNA.[2] The poly(A) tail is located on the 3' end of mRNA. The nuclear isoforms selectively binds to around 50 nucleotides and stimulates the activity of Polyadenylate polymerase.

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 eukaryotes' Poly(A) binding protein binds to the initiation factor eIF-4G via its C-terminal domain. EIF-4G is bound to eIF-4E, another initiation factor bound to the 5' cap on the 5' end of mRNA. This binding forms the characteristic loop structure of eukaryotic protein synthesis. Poly(A)-binding protein interacting proteins in the cytosol compete for the eIF-4G binding sites. Poly(A)-binding protein has also been shown to interact with a termination factor (eRF3)

Rotavirus NSP3

Cellular vs Rotavirus Translation

Rotavirus RNA-binding protein NSP3 interacts with eIF4GI and evicts the poly(A) binding protein from eIF4F. And NSP3A, by taking the place of PABP on eIF4GI, is responsible for the shut-off of cellular protein synthesis.[3]

Genes

There are several forms.[4] These include:

References

  1. ^ Kahvejian A, Svitkin YV, Sukarieh R, M'Boutchou MN, Sonenberg N (January 2005). "Mammalian poly(A)-binding protein is a eukaryotic translation initiation factor, which acts via multiple mechanisms". Genes Dev. 19 (1): 104–13. doi:10.1101/gad.1262905. PMC 540229. PMID 15630022.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  2. ^ Poly(A)-Binding+Proteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
  3. ^ Piron, M; Vende, P; Cohen, J; Poncet, D (1998). "Rotavirus RNA-binding protein NSP3 interacts with eIF4GI and evicts the poly(A) binding protein from eIF4F" (Free full text). The EMBO Journal. 17 (19): 5811–21. doi:10.1093/emboj/17.19.5811. PMC 1170909. PMID 9755181.
  4. ^ Katzenellenbogen RA, Vliet-Gregg P, Xu M, Galloway DA (December 2010). "Cytoplasmic Poly(A) Binding Proteins Regulate Telomerase Activity and Cell Growth in Human Papillomavirus Type 16 E6-Expressing Keratinocytes". J. Virol. 84 (24): 12934–44. doi:10.1128/JVI.01377-10. PMC 3004306. PMID 20943973.{{cite journal}}: CS1 maint: multiple names: authors list (link)