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Wortman, Margaret J.; Dagdanova, Ayuna V.; Clark, Andrea M.; Godfrey, Earl W.; Pascal, Steven M.; Johnson, Edward M.; Daniel, Dianne C.
Biochimica et biophysica acta. Molecular cell research, 06/2020, Letnik: 1867, Številka: 6Journal Article
Increased Pur-alpha (Pura) protein levels in animal models alleviate certain cellular symptoms of the disease spectrum amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD). Pura is a member of the Pur family of evolutionarily conserved guanine-rich polynucleotide binding proteins containing a repeated signature PUR domain of 60–80 amino acids. Here we have employed a synthetic peptide, TZIP, similar to a Pur domain, but with sequence alterations based on a consensus of evolutionarily conserved Pur family binding domains and having an added transporter sequence. A major familial form of ALS/FTD, C9orf72 (C9), is due to a hexanucleotide repeat expansion (HRE) of (GGGGCC), a Pur binding element. We show by circular dichroism that RNA oligonucleotides containing this purine-rich sequence consist largely of parallel G-quadruplexes. TZIP peptide binds this repeat sequence in both DNA and RNA. It binds the RNA element, including the G-quadruplexes, with a high degree of specificity versus a random oligonucleotide. In addition, TZIP binds both linear and G-quadruplex repeat RNA to form higher order G-quadruplex secondary structures. This change in conformational form by Pur-based peptide represents a new mechanism for regulating G quadruplex secondary structure within the C9 repeat. TZIP modulation of C9 RNA structural configuration may alter interaction of the complex with other proteins. This Pur-based mechanism provides new targets for therapy, and it may help to explain Pura alleviation of certain cellular pathological aspects of ALS/FTD. •Pur-based peptide, TZIP, binds the hexanucleotide repeat expanded in C9orf72 ALS/FTD.•Circular dichroism analysis of C9orf72 repeat RNA reveals parallel G-quadruplexes.•TZIP binds both linear and G-quadruplex forms of the C9orf72 RNA repeat sequence.•TZIP binding alters the configuration of the G-quadruplex RNA secondary structure.•Our results may help reveal Pur-based motifs protective in repeat expansion diseases.
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Leto | Faktor vpliva | Izdaja | Kategorija | Razvrstitev | ||||
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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