A synthetic Pur-based peptide binds and alters G-quadruplex secondary structure present in the expanded RNA repeat of C9orf72 ALS/FTD

Margaret J. Wortman, Ayuna V. Dagdanova, Andrea M. Clark, Earl W. Godfrey, Steven M. Pascal, Edward M. Johnson, Dianne C. Daniel

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

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.

Original languageEnglish
Article number118674
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1867
Issue number6
DOIs
StatePublished - Jun 2020
Externally publishedYes

Keywords

  • Amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD)
  • Circular dichroism (CD)
  • Fragile X syndrome
  • G-quadruplex
  • Hexanucleotide repeat expansion (HRE)
  • Pur-alpha (Pura)

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