Bioch: Rna And Rna Processing

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Alternative mRNA splicing

Back 1

Some exons are deliberately skipped or included only some of the time.
*1/3-1/2 of all human genes are alternatively spliced to generate variant proteins.

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Exon Shuffling

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New genes from old parts
*

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a2 procollagen gene

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Demonstrates how mRNA splicing makes it possible to put new genes together by RECOMBINATION at the DNA level.

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Collagen

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long, strong, relatively rigid molecules that hold us together

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Collagen gets strength from:

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By forming a triple helix of three identical protein strands encoded by a single gene. This requires that a special triple-helix-forming protein sequence be repeated many times without interruption throughout the ORF.

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What compensates for random DNA recombination?

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The extreme precision of mRNA splicing
*The genome shuffles the exon deck at the DNA level, and mRNA processing then purges the random sequences by neatly joining the exons together.

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Which two processes must work together in building new genes from old pieces?

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Exon Shuffling and Alternative mRNA Splicing

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What process is ideally suited to building complex, multidomain proteins that tether different structural and/or functional units together?

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Exon Shuffling

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Translational Control

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Mechanisms that determine whether mRNA will be translated or not, and how quickly the mRNA will be degraded

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One of the most remarkable instances of translational control:

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How our body decides to store or use dietary iron.

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Iron circulates in blood bound to

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Transferrin (a protein)

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When iron is abundant, it is stored in:

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The iron-rich protein Ferritin

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When iron is scarce:

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Iron is imported from the blood into the cell in a 2-step process

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Two-step process of importing iron from the blood into the cell

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1: Transferrin first binds to transferrin receptor on cell surface
2: The complex is then internalized, releasing bound iron.

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What is responsible for both the NEGATIVE translational control of the ferritin mRNA and POSITIVE translational control of the transferrin receptor mRNA when iron is scarce?

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Iron Binding Protein (IBP)

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What do AU-rich motifs in the 3' untranslated region (3' UTR) have the ability to govern?

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mRNA stability

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AUUUA-rich motifs are typically found in mRNAs encoding:

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Proteins that are transiently expressed (ie. c-fos or cytokines such as GMCSF)

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Alternative Polyadenylation also controls flow of information from:

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gene to mRNA

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Immature B Cells rearrange:
*This results in

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Their immunoglobulin variable regions
*Nearly every B Cell creates a variable region specific for a different antigen

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IgM

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Cell surface immunoglobulin (displayed on immature B cells)
*Advertises antigen specificity

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Clonal Expansion

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When a cognate antigen interacts with the cell surface IgM, the awakening B cell also begins to secrete IgM antibody with the SAME variable region as the cell surface IgM

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The switch from membrane-bound to secreted IgM reflects:

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A small change in the relative efficiency of mRNA splicing and cotranscriptional polyadenylation.

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When the CstF64 polyadenylation factor is LOW (as in B cells not stimulated by antigen):

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*The second of two tandem poly(A) sites in the antibody heavy chain gene is used
*Splicing then simultaneously deletes mRNA sequences encoding the secreted C-terminal tail and attaches the Cu coding region to a membrane-spanning C-terminal tail.
*Result = IgM retained in membrane and displayed on cell surface

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When CstF64 is HIGH (as in activated B cells):

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*Polyadenylation occurs at the first of two tandem poly(A) sites
*Heavy chains have C-terminus for secretion

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Language of mRNA =

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Ribonucleotide sequence

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Language of proteins =

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An amino acid sequence

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What is the relative contribution, by mass, of RNA and protein to the Ribosome?

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Each contribute about half

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What is the only available catalyst for peptide bond formation in the peptidyltransferase center?

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Ribosomal RNA

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Peptidyltransferase Center

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Where new peptide bonds are made between the nascent polypeptide and the next amino acid

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Many antibiotics... (related to RNA)

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Target conserved ribosomal RNA sequences surrounding the peptidyltransferase enter, or block the nearby exit port through the ribosome for the growing polypeptide chain.

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3 Main principles of RNA folding, which generate 3D RNA structures:

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1:Form all local helices possible
2:Stack adjacent helices on each other to create uninterrupted coaxially stacked helices
3:Allow loops in local units of structure to interact with each other or with single-stranded regions

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Ribozymes

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The smallest RNA catalysts
*Found in RNA viruses

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What is the major human pathogen that has circular single-stranded RNA genomes?

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Hepatitis (sigma?) virus, associated with fulminant hepatitis

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Circular single-stranded RNA genomes are replicated by:

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Cellular RNA polymerases that go around and around the circular RNA template, copying it into a long multimeric strand
*These strands can cleave themselves into genome length monomeric units, even in the absence of protien!

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What is the evidence that RNA itself must be a ribozyme?

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The fact that multimeric RNA strands can cleave themselves into genome length monomeric units in the absence of protein.

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RNA backbone consists of:
*The chain is linked by what type of bond?
*How does the backbone alternate?

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Alternating ribose sugars and phosphophates, where each phosphate is linked to two flanking sugars through ester bonds
*Phosphodiester bonds
*Sugar-phosphate-sugar-phosphate-sugar-phosphate wehre a nucleotide base is attached to each sugar

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What does the overall fold of the RNA precisely position?

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The negatively charges phosphates and the nucleotide bases

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Once positioned by the folded RNA, the chelated magnesium cations and the nucleotide bases can...

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Catalyze cleavage or rearrangement of an RNA chain

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All known natural RNA-catalyzed reactions are variations on a single theme:

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The hydroxyl group of one molecule attacks a phosphodiester bond in another

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When the attacking hydroxyl group belongs to water (H-O-H), the result is?

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Hydrolysis of the phosphodiester bond

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When the attacking group belongs to another RNA molecule (RNA-OH), the result is?

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An RNA rearrangement

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When the attacking hydroxyl not only belongs to RNA but is an internal 2'-OH instead of a 3'-terminal 3'-OH, the result is?

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A lariat RNA

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All natural ribozymes use the this mechanism:

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the attacking hydroxyl group expels the other hydroxyl group, making a new bond as it breaks the old bond

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Folded RNA precisely positions the negatively charged phosphates, the nucleotide bases, and the magnesiums to create:

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An enzyme that functions much like one made entirely of protein!

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Three flavors of alternative mRNA Splicing

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1:Default splicing pattern
2:Exon skipping or exclusion (+/- exon 2)
3:Alternative exons (include exon 2 or 3)

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mRNA precursors are spliced by:

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5 small ribonucleoprotein (RNP) complexes
*snRNPs

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RNPs that splice mRNA

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snRNPs (snall nuclear ribnucleoprotein particles) "snurps"
*5 of them
*U1
*U2
*U4/U6
*U5
Each named for the small nuclear RNA (snRNA) within it

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The 5 snRNPs assemble onto the mRNA precursor, with U1 snRNP initially recognizing ? and U2 snRNP ?

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The 5' splice site
The branch site near the 3' splice site

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In mRNA splicing, what dissociates from U6 snRNA, freeing U6 to join with U2 snRNA as catalysts for the reaction?

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U4 snRNA

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mRNA splicing occurs in 2 steps within the spliceosome:

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1:Internal 2' hydroxyl group of the branch site attacks the 5' splice site, breaking the old bond and making a new one. This generates a free 5' exon (held tightly by the spliceosome) and a lariat intron.
2: The free 5' exon attacks the 3' splice site, again breaking an old bond and making a new one. This joins the two exons and releases the intron lariat, which is subsequently debranched and degraded

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snRNA components of the RNPs not only recognize key splicing signals in the mRNA precursor such as the 5' and 3' splice sites by base pairing with them, but also:

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Catalyze the actual making, breaking, and rearrangement of phosphoester bonds in the RNA backbone. Thus, the spliceosome, like the ribesome, is a ribozyme.

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Like the ribosome, what else functions as a ribozyme?

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the spliceosome

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What helps to ensure the speed and accuracy of the splicing reaction in mRNA splicing?

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The protein components of the snRNPs, and many auxiliary proteins that are not snRNP components