User:Ben Dawson/Sandbox1
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'''RNA Recognition Motifs (RRMs)''' | '''RNA Recognition Motifs (RRMs)''' | ||
| - | The <scene name='78/782616/Subunits_of_pabp/3'>Components of PABP</scene> are categorized into two RRMs: the n-terminus RRM1 (red) and c-terminus RRM2 (blue) are shown accordingly. The two RRMs are linked via an alpha-helix linker (green) that maintains the RRM1/2 complex that is the biological assembly and active form of PABP. Each RRM has a four-stranded antiparallel beta sheet backed by two corresponding alpha helices. <ref name="Recognition of Polyadenylate RNA by the Poly(A)-Binding Protein">Deo, Rahul C, et al. “Recognition of Polyadenylate RNA by the Poly(A)-Binding Protein.” Cell 98:6. (1999) 835-845. Print. </ref> mRNA poly-adenosine recognition is due to the presence of the conserved residues within the beta-sheet surface <ref name="The Poly(A)-Binding Protein and an mRNA Stability Protein Jointly Regulate an Endoribonuclease Activity.">Wang, Zuoren and Kiledjian, Megerditch. “The Poly(A)-Binding Protein and an mRNA Stability Protein Jointly Regulate an Endoribonuclease Activity.” Molecular and Cellular Biology 20.17 (2000): 6334–6341. Print.</ref> , which forms a <scene name='78/782616/Trough2/1'>trough</scene>-like pocket for the mRNA to bind. The beta-sheet flooring present in PABP interacts with the 3’ mRNA tail via | + | The <scene name='78/782616/Subunits_of_pabp/3'>Components of PABP</scene> are categorized into two RRMs: the n-terminus RRM1 (red) and c-terminus RRM2 (blue) are shown accordingly. The two RRMs are linked via an alpha-helix linker (green) that maintains the RRM1/2 complex that is the biological assembly and active form of PABP. Each RRM has a four-stranded antiparallel beta sheet backed by two corresponding alpha helices. <ref name="Recognition of Polyadenylate RNA by the Poly(A)-Binding Protein">Deo, Rahul C, et al. “Recognition of Polyadenylate RNA by the Poly(A)-Binding Protein.” Cell 98:6. (1999) 835-845. Print. </ref> mRNA poly-adenosine recognition is due to the presence of the conserved residues within the beta-sheet surface <ref name="The Poly(A)-Binding Protein and an mRNA Stability Protein Jointly Regulate an Endoribonuclease Activity.">Wang, Zuoren and Kiledjian, Megerditch. “The Poly(A)-Binding Protein and an mRNA Stability Protein Jointly Regulate an Endoribonuclease Activity.” Molecular and Cellular Biology 20.17 (2000): 6334–6341. Print.</ref> , which forms a <scene name='78/782616/Trough2/1'>trough</scene>-like pocket for the mRNA to bind. The beta-sheet flooring present in PABP interacts with the 3’ mRNA tail via combination of van der Waals, aromatic stacking, and Hydrogen bonding. Through these interactions, PABP binds to 3’ Poly (A) tail with a KD of 2-7 nM. <ref name="Roles of Cytoplasmic Poly(A)-Binding Proteins">Gorgoni, Barbra, and Gray, Nicola. “The Roles of Cytoplasmic Poly(A)-Binding Proteins in Regulating Gene Expression: A Developmental Perspective.” Briefings in Functional Genomics and Proteomics, vol. 3, no. 2, 1 Aug. 2004, pp. 125–141., doi:10.1093/bfgp/3.2.125.</ref> [[Image:Hydrophobicity (1).png|200px|right|thumb| "Figure 1:" Surface hydrophobicity shown in presence of mRNA]] |
Revision as of 18:46, 20 April 2018
Contents |
Human Poly(A) Binding Protein (1CVJ)
Background
The Human Poly(A) Binding Protein (PABP) was discovered in 1973 by the use of a sedimentation profile detailing the RNase digestion differentiated the PABP protein. [1] Attempts to purify the 75 kDa protein then followed. In 1983, then considered “poly(A)-organizing protein,” was determined and purified by molecular weight, ligand-binding affinity, and amounts found in cytoplasmic portions of cell with ability to bind to free poly(A). [2]
PABP is a mRNA binding protein that binds to the 3’ Poly(A) tail on mRNA. It is comprised of four RNA recognition motifs (RRMs), which are highly conserved RNA-binding domains.[3] The RRM in PABP is found in over two hundred families of proteins across species, indicating that it is ancient.[3] Through extensive Adenosine recognition by the RRMs of PABP, the protein is involved in three main functions: recognition of the 3’ Poly(A) tail, mRNA stabilization, and eukaryotic translation initiation. The contributions of controlling gene expression via different families of PABPs is not yet fully understood. PABP families are divided into nuclear and cytoplasmic. [4] PABP1, which is predominantly cytoplasmic, is often referred to as PABP because it is the only form of PABP that has been extensively studied in its role with mRNA translation and stability. [4]
Structure, Interactions, Function
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Disease and Medical Relevance
Oculopharyngeal Muscular Dystrophy
Oculopharyngeal muscular dystrophy, or OPMD, is an autosomal dominant late-onset disease. [7] It’s characterized by the myopathy of the eyelids and the throat. The symptoms entail eye-drooping and difficulty swallowing. There are two types of OPMD: autosomal dominant and recessive, both originating from the mutation of the PABP nuclear 1 (PABPN1) gene located on the long arm of chromosome 14. [7] This mutation results in an abnormally long polyalanine tract, 11-18 alanines, opposed to the normal 10. [7] Patients with longer PABPN1 expansion (more alanines) are on average diagnosed at an earlier in life than patients with a shorter expansion; therefore, expansion size plays a role in OPMD severity and progression. [8]
The mutation results in PABPN1 forming clumps in muscle cells that can’t be degraded. [7] It’s suspected that this is a source of cell death for effected cells, however, it has not been concluded why this mutation only affects certain muscle cells.
Studies on Mutations
Studies conducted on Drosophila are common due to 75% conservation between human and Drosophila genomes. Drosophila only encode one cytoplasmic PABP, and its deletion results in embryonic lethality. [4] Similarly, in Caenorhabditis elegans, which have two cytoplasmic PABPs, display 50-80% embryonic lethality with the introduction of an RNAi to one of these PABPs. [4]
References
- ↑ Blobel, Gunter. “A Protein of Molecular Weight 78,000 Bound to the Polyadenylate Region of Eukaryotic Messenger Rnas.” Proceedings of the National Academy of Sciences of the United States of America, vol. 70, no. 3, 1973, pp. 924–8.
- ↑ Baer, Bradford W. and Kornberg, Roger D. "The Protein Responsible for the Repeating Structure of Cytoplasmic Poly(A)-Ribonucleoprotein." The Journal of Cell Biology, vol. 96, no. 3, Mar. 1983, pp. 717-721. EBSCOhost.
- ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 Deo, Rahul C, et al. “Recognition of Polyadenylate RNA by the Poly(A)-Binding Protein.” Cell 98:6. (1999) 835-845. Print.
- ↑ 4.0 4.1 4.2 4.3 4.4 Gorgoni, Barbra, and Gray, Nicola. “The Roles of Cytoplasmic Poly(A)-Binding Proteins in Regulating Gene Expression: A Developmental Perspective.” Briefings in Functional Genomics and Proteomics, vol. 3, no. 2, 1 Aug. 2004, pp. 125–141., doi:10.1093/bfgp/3.2.125.
- ↑ Kühn, Uwe and Elmar, Wahle. “Structure and Function of Poly(a) Binding Proteins.” Bba - Gene Structure & Expression, vol. 1678, no. 2/3, 2004.
- ↑ Wang, Zuoren and Kiledjian, Megerditch. “The Poly(A)-Binding Protein and an mRNA Stability Protein Jointly Regulate an Endoribonuclease Activity.” Molecular and Cellular Biology 20.17 (2000): 6334–6341. Print.
- ↑ 7.0 7.1 7.2 7.3 “Oculopharyngeal Muscular Dystrophy.” NORD (National Organization for Rare Disorders), rarediseases.org/rare-diseases/oculopharyngeal-muscular-dystrophy/.
- ↑ Richard, Pascale, et al. “Correlation between PABPN1 Genotype and Disease Severity in Oculopharyngeal Muscular Dystrophy.” Neurology, vol. 88, no. 4, 2016, pp. 359–365., doi:10.1212/wnl.0000000000003554.
