Aberrant phase separation is a common killing strategy of positively charged peptides in biology and human disease.
LL-37
Phase separation
RAN translation
amyotrophic lateral sclerosis
antimicrobial peptide
cathelicidin
crotamine
frontotemporal dementia
membraneless organelles
protein aggregation
Journal
bioRxiv : the preprint server for biology
Titre abrégé: bioRxiv
Pays: United States
ID NLM: 101680187
Informations de publication
Date de publication:
09 Mar 2023
09 Mar 2023
Historique:
pubmed:
23
3
2023
medline:
23
3
2023
entrez:
22
3
2023
Statut:
epublish
Résumé
Positively charged repeat peptides are emerging as key players in neurodegenerative diseases. These peptides can perturb diverse cellular pathways but a unifying framework for how such promiscuous toxicity arises has remained elusive. We used mass-spectrometry-based proteomics to define the protein targets of these neurotoxic peptides and found that they all share similar sequence features that drive their aberrant condensation with these positively charged peptides. We trained a machine learning algorithm to detect such sequence features and unexpectedly discovered that this mode of toxicity is not limited to human repeat expansion disorders but has evolved countless times across the tree of life in the form of cationic antimicrobial and venom peptides. We demonstrate that an excess in positive charge is necessary and sufficient for this killer activity, which we name 'polycation poisoning'. These findings reveal an ancient and conserved mechanism and inform ways to leverage its design rules for new generations of bioactive peptides.
Identifiants
pubmed: 36945394
doi: 10.1101/2023.03.09.531820
pmc: PMC10028949
pii:
doi:
Types de publication
Preprint
Langues
eng
Subventions
Organisme : NIGMS NIH HHS
ID : P30 GM138441
Pays : United States
Organisme : NINDS NIH HHS
ID : P30 NS069375
Pays : United States
Organisme : NIGMS NIH HHS
ID : P41 GM103445
Pays : United States
Organisme : NINDS NIH HHS
ID : R35 NS097263
Pays : United States
Déclaration de conflit d'intérêts
DECLARATION OF INTERESTS: A.D.G has served as a consultant for Aquinnah Pharmaceuticals, Prevail Therapeutics, and Third Rock Ventures and is a scientific founder of Maze Therapeutics. A.C.O. is a co-founder of Werewool. All other authors declare no competing interests. A.S.H. is a scientific consultant for Dewpoint Therapeutics and on the Scientific Advisory Board for Prose Foods.
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