Protonation-dependent conformational variability of intrinsically disordered proteins

Area of Science:

• Biochemistry
• Structural Biology
• Biophysics

Background:

• Intrinsically disordered proteins (IDPs) exhibit significant conformational plasticity, altering their structure in response to environmental changes like pH.
• Unlike folded proteins, IDPs often adopt compact conformations at acidic pH, a phenomenon observed in proteins like alpha-synuclein.

Purpose of the Study:

• To conduct a large-scale analysis of how pH affects the structure of intrinsically disordered proteins.
• To investigate the tendency of IDPs to form specific secondary structures and overall compactness under varying pH conditions.

Main Methods:

• Utilized a recently developed meta-structure approach for analyzing a large dataset of IDPs.
• Applied the meta-structure analysis to assess pH-dependent structural changes, including secondary structure formation and conformational compactness.

Main Results:

• Demonstrated a significant tendency for IDPs to form alpha-helical secondary structures under acidic conditions.
• Revealed that IDPs preferentially fold into more compact structures when exposed to acidic environments.
• Validated the meta-structure approach using specific examples like the tumor suppressor BASP1 and transcription factor Tcf4.

Conclusions:

• The meta-structure approach provides a predictive framework for understanding pH-dependent structural transitions in IDPs.
• Acidic conditions promote specific structural rearrangements in IDPs, leading to increased alpha-helicity and compactness.
• These findings enhance our understanding of IDP behavior and have implications for studying proteins involved in various biological processes.