Tyr10 Modifications and Peptide Context Rewire GLP-1 Modulation of Amyloid-β42 Assembly
- 1Institute of Chemistry
- 2Humboldt-Universität zu Berlin Brook-Taylor-Str. 2, 12489 Berlin
Abstract
Glucagon-like peptide-1 (GLP-1) is best known as a receptor agonist, yet its peptide-level behavior in protein-rich environments remains poorly defined. Here, a GLP-1-directed photoaffinity probe recovered a predefined Aβ42 spike-in from cell lysates, while endogenous actin and α-synuclein were detected in the recovered fractions. This observation motivated chemically defined assembly studies with the actinlinked β-thymosin reference TMSB4Y. Thioflavin T (ThT) kinetics and endpoint electron microscopy (EM) revealed no single pro- or antiassembly response. GLP-1 advanced the ThT-positive transition of Tyr10-unmodified Aβ42, whereas TMSB4Y attenuated it. Phosphorylation or nitration at Tyr10 changed both the direction and timing of these effects, and GLP-1 added after assembly had begun redirected established trajectories in a Tyr10-modification-dependent manner. Ser18 O-GlcNAcylation of GLP-1 provided an orthogonal perturbation, suppressing the Tyr10-unmodified response while enhancing the nitrated trajectory and delaying the phosphorylated one. Together, capture in a complex protein background and assembly in defined mixtures identify GLP-1 as a context-sensitive modulator of Aβ42 assembly rather than a fixed promoter or inhibitor.
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BibTeX
@misc{ghosh2026tyr10,
title = {{Tyr10 Modifications and Peptide Context Rewire GLP-1 Modulation of Amyloid-β42 Assembly}},
author = {Pritam Ghosh},
howpublished = {ChemRxiv},
year = {2026},
month = oct,
doi = {10.26434/chemrxiv.15010165/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010165/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Tyr10 Modifications and Peptide Context Rewire GLP-1 Modulation of Amyloid-β42 Assembly
AU - Pritam Ghosh
PY - 2026
DA - 2026/10/09
PB - ChemRxiv
DO - 10.26434/chemrxiv.15010165/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010165/v1
AB - Glucagon-like peptide-1 (GLP-1) is best known as a receptor agonist, yet its peptide-level behavior in protein-rich environments remains poorly defined. Here, a GLP-1-directed photoaffinity probe recovered a predefined Aβ42 spike-in from cell lysates, while endogenous actin and α-synuclein were detected in the recovered fractions. This observation motivated chemically defined assembly studies with the actinlinked β-thymosin reference TMSB4Y. Thioflavin T (ThT) kinetics and endpoint electron microscopy (EM) revealed no single pro- or antiassembly response. GLP-1 advanced the ThT-positive transition of Tyr10-unmodified Aβ42, whereas TMSB4Y attenuated it. Phosphorylation or nitration at Tyr10 changed both the direction and timing of these effects, and GLP-1 added after assembly had begun redirected established trajectories in a Tyr10-modification-dependent manner. Ser18 O-GlcNAcylation of GLP-1 provided an orthogonal perturbation, suppressing the Tyr10-unmodified response while enhancing the nitrated trajectory and delaying the phosphorylated one. Together, capture in a complex protein background and assembly in defined mixtures identify GLP-1 as a context-sensitive modulator of Aβ42 assembly rather than a fixed promoter or inhibitor.
ER -