Identification and characterization of cytotoxic amyloid-like regions in human Pbx-regulating protein-1

Nunzianna Doti, Alessandra Monti, Chiara Bruckmann, Luisa Calvanese, Giovanni Smaldone, Andrea Caporale, Lucia Falcigno, Gabriella D'Auria, Francesco Blasi, Menotti Ruvo, Luigi Vitagliano

Research output: Contribution to journalArticlepeer-review

Abstract

The ability of many proteins to fold into well-defined structures has been traditionally considered a prerequisite for fulfilling their functions. Protein folding is also regarded as a valuable loophole to escape uncontrolled and harmful aggregations. Here we show that the PBX-regulating protein-1 (PREP1), an important homeodomain transcription factor involved in cell growth and differentiation during embryogenesis, is endowed with an uncommon thermostability. Indeed, circular dichroism analyses indicate that it retains most of its secondary structure at very high temperatures. These findings have important implications for PREP1 functions since it is a stabilizing factor of its partner PBX1. Predictive analyses suggest that the observed PREP1 thermostability could be related to the presence of aggregation-prone regions. Interestingly, synthetic peptides corresponding to these regions exhibit a remarkable propensity to form toxic β-rich amyloid-like aggregates in physiological conditions. On this basis, we suggest that PREP1 stability is an effective way to prevent or limit the formation of harmful aggregates. Notably, one of these PREP1 fragments (residues 117-132) is able to reversibly switch from α-helical to β-rich states depending on the environmental conditions. The chameleon conformational behavior of this peptide makes it an ideal system to study this intriguing and widespread structural transition.

Original languageEnglish
Pages (from-to)618-629
Number of pages12
JournalInternational Journal of Biological Macromolecules
Volume163
DOIs
Publication statusPublished - Nov 15 2020

Keywords

  • NMR
  • PREP1
  • Protein aggregation-prone regions (APRs)
  • Thioflavin-T fluorescence assay
  • Tumor diagnosis

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Economics and Econometrics
  • Energy(all)

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