Using in vivo intact structure for system-wide quantitative analysis of changes in proteins.

Autor: Son A; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, USA., Kim H; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, USA.; Department of Convergent Bioscience and Informatics, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon, Republic of Korea., Diedrich JK; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, USA., Bamberger C; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, USA., McClatchy DB; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, USA., Lipton SA; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, USA.; Neurodegeneration New Medicines Center, The Scripps Research Institute, La Jolla, CA, USA.; Department of Neurosciences School of Medicine University of California, San Diego, La Jolla, CA, USA., Yates JR; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, USA. jyates@scripps.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Oct 29; Vol. 15 (1), pp. 9310. Date of Electronic Publication: 2024 Oct 29.
DOI: 10.1038/s41467-024-53582-x
Abstrakt: Mass spectrometry-based methods can provide a global expression profile and structural readout of proteins in complex systems. Preserving the in vivo conformation of proteins in their innate state is challenging during proteomic experiments. Here, we introduce a whole animal in vivo protein footprinting method using perfusion of reagents to add dimethyl labels to exposed lysine residues on intact proteins which provides information about protein conformation. When this approach is used to measure dynamic structural changes during Alzheimer's disease (AD) progression in a mouse model, we detect 433 proteins that undergo structural changes attributed to AD, independent of aging, across 7 tissues. We identify structural changes of co-expressed proteins and link the communities of these proteins to their biological functions. Our findings show that structural alterations of proteins precede changes in expression, thereby demonstrating the value of in vivo protein conformation measurement. Our method represents a strategy for untangling mechanisms of proteostasis dysfunction caused by protein misfolding. In vivo whole-animal footprinting should have broad applicability for discovering conformational changes in systemic diseases and for the design of therapeutic interventions.
(© 2024. The Author(s).)
Databáze: MEDLINE
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