Poly(A)-binding protein
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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 and is 200-250 nucleotides long. The binding protein is also involved in mRNA precursors by helping Polyadenylate polyermase add the Poly(A) nucleotide tail to the pre-mRNA before translation.[3] The nuclear 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.[4]
Poly(A) Binding Protein Structure
Cytosolic Poly-A Binding Protein (PABPC) is made up of four 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 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’s 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.[5] 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.[6] 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 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 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
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.[7]
Genes
There are several forms.[8] These include:
References
- ^ 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) - ^ Poly(A)-Binding+Proteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- ^ "UniProtKB - Q86U42 (PABP2_HUMAN)". uniprot.org. Retrieved 17 November 2015.
- ^ Voet, Donald; Voet, Judith. Biochemistry (4 ed.). Wiley. p. 1304.
- ^ Deo, Rahul (Sep 1999). "Recognition of Polyadenylate RNA by the Poly(A)-Binding Protein". Cell (Cambridge,Mass.). 98: 835-845. PMID 10499800.
- ^ Goss, DJ; Kleiman, FE (2013). "Poly(A) binding proteins: are they all created equal?". Wiley Interdisciplinary Review. RNA.: 167-179. doi:10.1002/wrna. PMID 23424172.
- ^ 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.
- ^ 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)
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