Alpha-synuclein: stable compact and extended monomeric structures and pH dependence of dimer formation

Area of Science:

• Biochemistry
• Structural Biology
• Analytical Chemistry

Background:

• Alpha-synuclein is a protein linked to Parkinson's disease.
• Understanding its structural dynamics is crucial for disease research.

Purpose of the Study:

• To investigate the structural changes of alpha-synuclein based on solution pH.
• To explore the relationship between protein charge, shape, and aggregation.

Main Methods:

• Utilized negative-ion nano-electrospray ionization (N-ESI) mass spectrometry.
• Employed ion mobility measurements to determine protein shape and size.
• Analyzed data across different spray solution pH levels (pH 7 and pH 2.5).

Main Results:

• Solution pH significantly impacts alpha-synuclein's charge-state distribution and overall protein structure.
• At pH 7, alpha-synuclein adopts extended conformations with higher negative charges and forms dimers.
• At pH 2.5, alpha-synuclein exhibits compact structures with fewer negative charges and no observed dimer formation.
• A 33% reduction in cross-section was observed for compact structures at pH 2.5 compared to extended structures at pH 7.

Conclusions:

• Alpha-synuclein exists in at least two distinct structural families (compact and extended) dependent on pH.
• These pH-dependent structural changes influence dimer formation and may provide insights into aggregate formation mechanisms in Parkinson's disease.
• The study highlights the importance of solution conditions in characterizing protein structure and function.