Tricking a Protein To Swap Strands

Area of Science:

• Biochemistry
• Structural Biology
• Neuroscience

Background:

• Partly unfolded proteins are implicated in human diseases like Amyotrophic Lateral Sclerosis (ALS).
• Understanding local structural transitions leading to protein aggregation is crucial but challenging.
• The specific aggregation pathway of SOD1, a protein linked to ALS, remains unclear.

Purpose of the Study:

• To develop a novel protein-design strategy for real-time detection of secondary structure element dynamics.
• To investigate the structural transitions of the SOD1 β-barrel during unfolding and aggregation.
• To elucidate the role of local versus global unfolding in protein aggregation relevant to neurodegenerative diseases.

Main Methods:

• A protein-design strategy enabling real-time observation of secondary structure element rupture and swapping.
• Application of this method to the dynamic β-barrel structure of Superoxide Dismutase 1 (SOD1).
• Experimental analysis of molecular events previously inaccessible to direct observation.

Main Results:

• Rupture and re-insertion of β-strands in SOD1 do not occur in isolation.
• Global unfolding of the SOD1 barrel is required for individual β-strand dynamics.
• Findings challenge the existence of partly unfolded intermediates in SOD1 aggregation.

Conclusions:

• The study questions the role of partly unfolded intermediates in SOD1-related aggregation.
• Hydrogen bonding plays a critical role in maintaining the global structural integrity of SOD1.
• New insights into the mechanisms underlying protein aggregation in neurodegenerative diseases like ALS are provided.