Polypyrimidine tract

Last updated April 02, 2020

The essential spliceosome component U2AF bound to a short polypyrimidine RNA fragment. Ppy-tract-2g4b.png — The essential spliceosome component U2AF bound to a short polypyrimidine RNA fragment.

The polypyrimidine tract is a region of pre-messenger RNA (mRNA) that promotes the assembly of the spliceosome, the protein complex specialized for carrying out RNA splicing during the process of post-transcriptional modification. The region is rich with pyrimidine nucleotides, especially uracil, and is usually 15–20 base pairs long, located about 5–40 base pairs before the 3' end of the intron to be spliced.^[1]

A number of protein factors bind to or associate with the polypyrimidine tract, including the spliceosome component U2AF and the polypyrimidine tract-binding protein (PTB), which plays a regulatory role in alternative splicing. PTB's primary function is in exon silencing, by which a particular exon region normally spliced into the mature mRNA is instead left out, resulting in the expression of an isoform of the protein for which the mRNA codes. Because PTB is ubiquitously expressed in many higher eukaryotes, it is thought to suppress the inclusion of "weak" exons with poorly defined splice sites.^[2] However, PTB binding is not sufficient to suppress "robust" exons.^[3]

The suppression or selection of exons is critical to the proper expression of tissue-specific isoforms. For example, smooth muscle and skeletal muscle express alternate isoforms distinguished by mutually exclusive exon selection in alpha-tropomyosin.^[4]

Related Research Articles

RNA splicing The maturation process of the primary RNA transcripts to remove intron sequences (not present in the mature form) and joining the remaining exon sections to form a mature messenger RNA

RNA splicing, in molecular biology, is a form of RNA processing in which a newly made precursor messenger RNA (pre-mRNA) transcript is transformed into a mature messenger RNA (mRNA). During splicing, introns are removed and exons are joined together. For nuclear-encoded genes, splicing takes place within the nucleus either during or immediately after transcription. For those eukaryotic genes that contain introns, splicing is usually required in order to create an mRNA molecule that can be translated into protein. For many eukaryotic introns, splicing is carried out in a series of reactions which are catalyzed by the spliceosome, a complex of small nuclear ribonucleo proteins (snRNPs). Self-splicing introns, or ribozymes capable of catalyzing their own excision from their parent RNA molecule, also exist.

The coding region of a gene, also known as the CDS, is the portion of a gene's DNA or RNA that codes for protein. Studying the length, composition, regulation, splicing, structures, and functions of coding regions compared to non-coding regions over different species and time periods can provide a significant amount of important information regarding gene organization and evolution of prokaryotes and eukaryotes. This can further assist in mapping the human genome and developing gene therapy.

Alternative splicing, or alternative RNA splicing, or differential splicing, is a regulated process during gene expression that results in a single gene coding for multiple proteins. In this process, particular exons of a gene may be included within or excluded from the final, processed messenger RNA (mRNA) produced from that gene. Consequently, the proteins translated from alternatively spliced mRNAs will contain differences in their amino acid sequence and, often, in their biological functions. Notably, alternative splicing allows the human genome to direct the synthesis of many more proteins than would be expected from its 20,000 protein-coding genes.

A spliceosome is a large and complex molecular machine found primarily within the nucleus of eukaryotic cells. The spliceosome is assembled from small nuclear RNAs (snRNA) and approximately 80 proteins. 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.

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.

Primary transcript RNA produced by transcription

A primary transcript is the single-stranded ribonucleic acid (RNA) product synthesized by transcription of DNA, and processed to yield various mature RNA products such as mRNAs, tRNAs, and rRNAs. The primary transcripts designated to be mRNAs are modified in preparation for translation. For example, a precursor mRNA (pre-mRNA) is a type of primary transcript that becomes a messenger RNA (mRNA) after processing.

Tropomyosin is a two-stranded alpha-helical coiled coil protein found in cell cytoskeletons.

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.

An exonic splicing silencer (ESS) is a short region of an exon and is a cis-regulatory element. A set of 103 hexanucleotides known as FAS-hex3 has been shown to be abundant in ESS regions. ESSs inhibit or silence splicing of the pre-mRNA and contribute to constitutive and alternate splicing. To elicit the silencing affect, ESSs recruit proteins that will negatively affect the core splicing machinery.

Polypyrimidine tract-binding protein, also known as PTB or hnRNP I, is an RNA-binding protein. PTB functions mainly as a splicing regulator, although it is also involved in alternative 3' end processing, mRNA stability and RNA localization.

Cardiac muscle troponin T (cTnT) is a protein that in humans is encoded by the TNNT2 gene. Cardiac TnT is the tropomyosin-binding subunit of the troponin complex, which is located on the thin filament of striated muscles and regulates muscle contraction in response to alterations in intracellular calcium ion concentration.

Tropomyosin alpha-1 chain is a protein that in humans is encoded by the TPM1 gene. This gene is a member of the tropomyosin (Tm) family of highly conserved, widely distributed actin-binding proteins involved in the contractile system of striated and smooth muscles and the cytoskeleton of non-muscle cells.

Tropomyosin alpha-3 chain is a protein that in humans is encoded by the TPM3 gene.

Splicing factor, proline- and glutamine-rich is a protein that in humans is encoded by the SFPQ gene.

β-Tropomyosin, also known as tropomyosin beta chain is a protein that in humans is encoded by the TPM2 gene. β-tropomyosin is striated muscle-specific coiled coil dimer that functions to stabilize actin filaments and regulate muscle contraction.

Troponin I, slow skeletal muscle is a protein that in humans is encoded by the TNNI1 gene. It is a tissue-specific subtype of troponin I, which in turn is a part of the troponin complex.

Slow skeletal muscle troponin T (sTnT) is a protein that in humans is encoded by the TNNT1 gene.

Far upstream element-binding protein 2 is a protein that in humans is encoded by the KHSRP gene.

Fast skeletal muscle troponin T (fTnT) is a protein that in humans is encoded by the TNNT3 gene.

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

References

↑ Lodish H, Berk A, Matsudaira P, Kaiser CA, Krieger M, Scott MP, Zipursky SL, Darnell J. (2004). Molecular Cell Biology. WH Freeman: New York, NY. 5th ed.
↑ Wagner EJ, Garcia-Blanco MA. (2001). Polypyrimidine tract binding protein antagonizes exon definition. Mol Cell Biol 21(10):3281-3288.
↑ Gooding C, Roberts GC, Smith CW. (1998). Role of an inhibitory pyrimidine element and polypyrimidine tract binding protein in repression of a regulated alpha-tropomyosin exon. RNA 4:85-100.
↑ Gooding C, Roberts GC, Moreau G, Nadal-Ginard B, Smith CW. (1994). Smooth muscle-specific switching of alpha-tropomyosin mutually exclusive exon selection by specific inhibition of the strong default exon. EMBO J 13(16):3861-72.

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[Lodish-1] Lodish H, Berk A, Matsudaira P, Kaiser CA, Krieger M, Scott MP, Zipursky SL, Darnell J. (2004). Molecular Cell Biology. WH Freeman: New York, NY. 5th ed.

[Wagner-2] Wagner EJ, Garcia-Blanco MA. (2001). Polypyrimidine tract binding protein antagonizes exon definition. Mol Cell Biol 21(10):3281-3288.

[Gooding-3] Gooding C, Roberts GC, Smith CW. (1998). Role of an inhibitory pyrimidine element and polypyrimidine tract binding protein in repression of a regulated alpha-tropomyosin exon. RNA 4:85-100.

[Gooding2-4] Gooding C, Roberts GC, Moreau G, Nadal-Ginard B, Smith CW. (1994). Smooth muscle-specific switching of alpha-tropomyosin mutually exclusive exon selection by specific inhibition of the strong default exon. EMBO J 13(16):3861-72.