The acidic pH-induced structural changes in Pin1 as revealed by spectral methodologies.

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Pin1 protein is implicated in the pathogenesis of cancers and Alzheimer's disease (AD).
• Previous studies characterized the thermal denaturation of Pin1.
• Understanding Pin1's response to acidic conditions is crucial for disease pathogenesis and therapeutic strategies.

Purpose of the Study:

• To investigate the acid-induced denaturation of Pin1.
• To elucidate the structural changes and their implications for Pin1's function.
• To explore the role of decreased pH in Pin1-related diseases.

Main Methods:

• Utilized fluorescence emission, synchronous fluorescence, far-UV circular dichroism (CD), ANS fluorescence, and Rayleigh light scattering (RLS) spectroscopies.
• Analyzed structural transitions across a range of acidic pH values.

Main Results:

• Observed partially reversible unfolding and refolding of Pin1 structures between pH 7.0 and 1.0, with an intermediate state around pH 4.0-4.5.
• Acidic pH below 4.0 induced a transition from α-helix and random coils to β-sheet structures.
• Below pH 2.3, hydrophobic side-chains were exposed, leading to Pin1 aggregation, possibly forming intermolecular β-sheets, and explaining activity loss below pH 5.0.

Conclusions:

• Acidic pH induces irreversible structural changes in Pin1, including hydrophobic exposure, α-helix to β-sheet transition, and aggregation.
• These structural alterations correlate with the loss of Pin1 activity at acidic pH.
• The findings highlight the significance of acidosis in Pin1-related diseases and support pH-modulating therapeutic approaches.