Using in vivo intact structure for system-wide quantitative analysis of changes in proteins.
Ahrum Son1, Hyunsoo Kim1,2, Jolene K Diedrich1
1Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, USA.
Nature Communications
|October 29, 2024
Summary
This study introduces a new whole-animal method to measure protein structure changes in vivo. This technique revealed structural alterations in 433 proteins during Alzheimer's disease progression, preceding expression changes.
Area of Science:
- Proteomics
- Structural Biology
- Neuroscience
Background:
- Mass spectrometry offers global protein expression and structural insights.
- Maintaining protein conformation during proteomic studies is difficult.
- Existing methods struggle to capture in vivo protein structure.
Purpose of the Study:
- To develop a whole-animal in vivo protein footprinting method.
- To investigate dynamic protein structural changes in Alzheimer's disease (AD).
- To link protein structural alterations to biological functions and disease mechanisms.
Main Methods:
- Developed a whole-animal in vivo protein footprinting technique.
- Used perfusion of reagents to label exposed lysine residues on intact proteins.
- Applied the method to a mouse model of Alzheimer's disease across seven tissues.
Main Results:
- Detected 433 proteins with structural changes attributed to AD, independent of aging.
- Identified structural changes in co-expressed protein communities.
- Observed that protein structural alterations precede changes in protein expression.
Conclusions:
- Protein structural changes occur early in Alzheimer's disease progression.
- The in vivo method provides insights into proteostasis dysfunction and protein misfolding.
- This approach is valuable for studying systemic diseases and designing therapeutics.
