Reframing prosegment-dependent folding and limits on natural protein folding landscapes from an evolutionary...

Area of Science:

• Biochemistry
• Molecular Biology
• Evolutionary Biology

Background:

• Proteases are crucial enzymes, but their folding mechanisms are not fully understood.
• Traditional protein folding models emphasize thermodynamic stability and rapid folding.
• Some proteases, like pepsin and alpha-lytic protease (αLP), exhibit unusual folding properties.

Purpose of the Study:

• To propose a new perspective on the folding energy landscapes of specific proteases.
• To challenge conventional protein folding principles by examining 'unevolved' landscapes.
• To explore the evolutionary and practical implications of these distinct folding strategies.

Main Methods:

• Comparative analysis of folding energy landscapes.
• Examination of kinetic and thermodynamic properties of proteases.
• Review of existing literature on protein folding exceptions.

Main Results:

• Pepsin and αLP folding landscapes are proposed as unevolved and distinct from their zymogen forms.
• These proteases display frustration hallmarks: non-cooperativity, memory effects, and kinetic trapping.
• This folding strategy deviates from general protein folding principles.

Conclusions:

• Proteins may evolve to utilize a wider range of energy landscapes than previously thought.
• This perspective offers insights into enzyme design, drug targets, and tunable folding landscapes.
• Growing examples of protein folding exceptions suggest a paradigm shift in understanding protein structure-function relationships.