Aberrant phase separation is a common killing strategy of positively charged peptides in biology and human disease.

Autor:	Boeynaems S; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.; Therapeutic Innovation Center (THINC), Baylor College of Medicine, Houston, TX 77030, USA.; Center for Alzheimer's and Neurodegenerative Diseases (CAND), Texas Children's Hospital, Houston, TX 77030, USA.; Dan L Duncan Comprehensive Cancer Center (DLDCCC), Baylor College of Medicine, Houston, TX 77030, USA.; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA., Ma XR; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA., Yeong V; Department of Chemical Engineering, Columbia University, New York, NY, 10027, USA., Ginell GM; Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA.; Center for Biomolecular Condensates, Washington University in St Louis, St. Louis, MO 63130, USA., Chen JH; Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.; Department of Anatomy, University of California, San Francisco, CA 94143, USA., Blum JA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA., Nakayama L; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA., Sanyal A; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA., Briner A; Clem Jones Centre for Ageing Dementia Research (CJCADR), Queensland Brain Institute (QBI), The University of Queensland, Brisbane, QLD 4072, Australia., Haver DV; VIB-UGent Center for Medical Biotechnology, 9000 Gent, Belgium.; VIB Proteomics Core, 9000 Gent, Belgium.; Department of Biochemistry, Ghent University, 9000 Gent, Belgium., Pauwels J; VIB-UGent Center for Medical Biotechnology, 9000 Gent, Belgium.; VIB Proteomics Core, 9000 Gent, Belgium.; Department of Biochemistry, Ghent University, 9000 Gent, Belgium., Ekman A; Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.; Department of Anatomy, University of California, San Francisco, CA 94143, USA., Schmidt HB; Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA., Sundararajan K; Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA., Porta L; Department of Pharmacology, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), Sao Paulo, Brazil., Lasker K; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA., Larabell C; Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.; Department of Anatomy, University of California, San Francisco, CA 94143, USA., Hayashi MAF; Department of Pharmacology, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), Sao Paulo, Brazil., Kundaje A; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.; Department of Computer Science, Stanford University, Stanford, CA 94305, USA., Impens F; VIB-UGent Center for Medical Biotechnology, 9000 Gent, Belgium.; VIB Proteomics Core, 9000 Gent, Belgium.; Department of Biochemistry, Ghent University, 9000 Gent, Belgium., Obermeyer A; Department of Chemical Engineering, Columbia University, New York, NY, 10027, USA., Holehouse AS; Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA.; Center for Biomolecular Condensates, Washington University in St Louis, St. Louis, MO 63130, USA., Gitler AD; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Mar 09. Date of Electronic Publication: 2023 Mar 09.
DOI:	10.1101/2023.03.09.531820
Abstrakt:	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. Competing Interests: 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.
Databáze:	MEDLINE
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