Submolecular Resolution of β‑Sheet Plasticity: Decoding Mutations and PTMs in Protein Aggregation Disorders.

Area of Science:

• Biophysics
• Protein Science
• Materials Science

Background:

• Protein functional diversity arises from conformational ensemble remodeling.
• Characterizing heterogeneous and transient protein ensembles is experimentally challenging.

Purpose of the Study:

• To determine beta-sheet conformational substates of hIAPP using scanning tunneling microscopy (STM).
• To investigate the effects of mutations and post-translational modifications (PTMs) on hIAPP beta-sheet conformational ensembles and aggregation propensity.

Main Methods:

• Utilized ultrahigh-resolution scanning tunneling microscopy (STM) to analyze beta-sheet structures.
• Introduced four specific mutations and PTMs to hIAPP to study their impact on assembly.

Main Results:

• Identified 17 types of beta-sheet conformational substates and 60 types of inter-conformation interactions in hIAPP.
• Observed that mutations and PTMs significantly regulate the number and type of conformational substates and alter the energy landscape of inter-strand interactions.
• Demonstrated a correlation between variations in beta-sheet conformational ensembles and divergent aggregation propensities.

Conclusions:

• Protein conformational ensembles exhibit significant plasticity in response to mutations and PTMs.
• STM provides unprecedented resolution for characterizing complex protein conformational dynamics.
• Understanding these dynamics is crucial for deciphering protein function and aggregation-related diseases.