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

Biochim Biophys Acta Mol Cell Res. 2020 Jun;1867(6):118674. doi: 10.1016/j.bbamcr.2020.118674. Epub 2020 Feb 6.


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.

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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • C9orf72 Protein / chemistry
  • C9orf72 Protein / genetics*
  • C9orf72 Protein / metabolism*
  • Circular Dichroism
  • DNA Repeat Expansion / drug effects
  • DNA-Binding Proteins / chemistry*
  • DNA-Binding Proteins / metabolism
  • G-Quadruplexes / drug effects
  • Humans
  • Models, Molecular
  • Molecular Mimicry
  • Peptides / chemical synthesis
  • Peptides / pharmacology*
  • RNA / chemistry
  • RNA / metabolism
  • Thermodynamics
  • Transcription Factors / chemistry*
  • Transcription Factors / metabolism


  • C9orf72 Protein
  • C9orf72 protein, human
  • DNA-Binding Proteins
  • PURA protein, human
  • Peptides
  • Transcription Factors
  • RNA