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RNA protein interactions governing expression of the most abundant protein in human body, type I collagen

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Type I collagen is the most abundant protein in human body. The protein turns over slowly and its replacement synthesis is low. However, in wound healing or in pathological fibrosis the cells can increase production of type I collagen several hundred fold. This increase is predominantly due to posttranscriptional regulation, including increased half‐life of collagen messenger RNAs (mRNAs) and their increased translatability. Type I collagen is composed of two α1 and one α2 polypeptides that fold into a triple helix. This stoichiometry is strictly regulated to prevent detrimental synthesis of α1 homotrimers. Collagen polypeptides are co‐translationally modified and the rate of modifications is in dynamic equilibrium with the rate of folding, suggesting coordinated translation of collagen α1(I) and α2(I) polypeptides. Collagen α1(I) mRNA has in the 3′ untranslated region (UTR) a C‐rich sequence that binds protein αCP, this binding stabilizes the mRNA in collagen producing cells. In the 5′ UTR both collagen mRNAs have a conserved stem‐loop (5′ SL) structure. The 5′ SL is critical for high collagen expression, knock in mice with disruption of the 5′ SL are resistant to liver fibrosis. the 5′ SL binds protein LARP6 with strict sequence specificity and high affinity. LARP6 recruits RNA helicase A to facilitate translation initiation and associates collagen mRNAs with vimentin and nonmuscle myosin filaments. Binding to vimentin stabilizes collagen mRNAs, while nonmuscle myosin regulates coordinated translation of α1(I) and α2(I) mRNAs. When nonmuscle myosin filaments are disrupted the cells secrete only α1 homotrimers. Thus, the mechanism governing high collagen expression involves two RNA binding proteins and development of cytoskeletal filaments. WIREs RNA 2013, 4:535–545. doi: 10.1002/wrna.1177 This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications Translation > Translation Regulation RNA Processing > 3' End Processing RNA Turnover and Surveillance > Regulation of RNA Stability

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5′ SL of human collagen α1(I) mRNA (H‐α1(I), left panel). Nucleotides involved in binding LARP6 are circled. Right panel: the consensus sequence of 5′ SL derived from all vertebrate collagen α1(I) and α2(I) mRNAs.
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LARP6 dependent synthesis of type I collagen. (a) Association of collagen mRNAs with cytoskeletal filaments. The process starts with binding of LARP6 to collagen mRNAs in the nucleus, what may facilitate their export to the cytoplasm. In the cytoplasm LARP6 associates collagen mRNAs with vimentin filaments or with nonmuscle myosin filaments. Shuttling of collagen mRNAs between these filaments is possible. Binding to vimentin stabilizes collagen mRNAs, while nonmuscle myosin filaments support their translation. (b) Coordinated translation of collagen mRNAs. The integrity of nonmuscle myosin filaments is necessary for translation to initiate on collagen α1(I) and α2(I) mRNAs in coordination. LARP6 recruits RHA to unwind the 5′ SL and collagen mRNAs are targeted to the membrane of the endoplasmic reticulum by the signal recognition particle or some other mechanism. Subsequent translation elongation takes place, resulting in increased local concentration of collagen polypeptides for productive folding into the collagen heterotrimer.
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Translation > Translation Regulation
RNA Turnover and Surveillance > Regulation of RNA Stability
RNA Processing > 3′ End Processing
RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications

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