Molecular mechanism of the inhibition of TDP-43 amyloidogenesis by QBP1
| Autor: | Daniel Ramírez de Mingo, Douglas V. Laurents, María del Carmen Fernández-Ramírez, Rubén Hervás, Mariano Carrión-Vázquez, Miguel Mompeán |
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| Přispěvatelé: | Fundación 'la Caixa', Ministerio de Economía y Competitividad (España) |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Amyloid Huntingtin Biophysics Biochemistry Fluorescence 03 medical and health sciences mental disorders medicine Humans Amino Acid Sequence Molecular Biology Peptide sequence 030102 biochemistry & molecular biology Chemistry Hydrogen bond Binding peptide DNA-Binding Proteins Glutamine 030104 developmental biology Mechanism of action Molecular mechanism medicine.symptom Oligopeptides |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| Popis: | Transactive Response DNA-Binding Protein of 43 kDa (TDP-43) is an essential human protein implicated in Amyotrophic Lateral Sclerosis (ALS) and common dementias. Its C-terminal disordered region, composed of residues 264–414 includes a hydrophobic segment (residues 320–340), which drives physiological liquid/liquid phase separation and a Q/N-rich segment (residues 341–357), which is essential for pathological amyloid formation. Due to TDP-43's relevance for pathology, identifying inhibitors and characterizing their mechanism of action are important pharmacological goals. The Polyglutamine Binding Peptide 1 (QBP1), whose minimal active core is the octapeptide WGWWPGIF, strongly inhibits the aggregation of polyQ-containing amyloidogenic proteins such as Huntingtin. Rather promiscuous, this inhibitor also blocks the aggregation of other glutamine containing amyloidogenic proteins, but not Aβ, and its mechanism of action remains unknown. Using a series of spectroscopic assays and biochemical tests, we establish that QBP1 binds and inhibits amyloid formation by TDP-43's Q/N-rich region. NMR spectroscopic data evince that the aromatic rings of QBP1 accept hydrogen bonds from the HN groups of the Asn and Gln to block amyloidogenesis. This mechanism of blockage may be general to polyphenol amyloid inhibitors. This study was supported by a Junior Leader Project LCF/BQ/PR19/11700003 (to MMG) from the Caixa Foundation (CID-100010434),and projects SAF2016-76678-C2-1-R (MC-V) and SAF2016-76678-C2-2-R(DVL) from the Spanish Ministry of Economy and Competitivity.NMR experiments were performed in the “Manuel Rico” NMR Laboratory (LMR) of the Spanish National Research Council (CSIC), a node of the Spanish Large-Scale National Facility (ICTSR-LRB). |
| Databáze: | OpenAIRE |
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