Sequence complexity of amyloidogenic regions in intrinsically disordered human proteins

Area of Science:

• Biochemistry
• Structural Biology
• Proteomics

Background:

• Amyloidogenic regions (ARs) are critical determinants of protein aggregation and amyloid formation.
• Intrinsically disordered proteins (IDPs) play crucial roles in cellular functions and are implicated in various diseases.
• Understanding the characteristics of ARs within IDPs is essential for deciphering disease mechanisms.

Purpose of the Study:

• To investigate the sequence complexity and characteristics of ARs in intrinsically disordered human proteins.
• To quantify the prevalence and length of ARs in disordered protein databases.
• To analyze the relationship between ARs, low-complexity regions (LCRs), and conformational adaptability.

Main Methods:

• Analysis of protein sequences from DisProt and IDEAL databases.
• Probability density distribution and discrete analysis of AR sequences.
• Assessment of sequence complexity and overlap with LCRs.
• Evaluation of conformational adaptability of AR residues (α-helix, β-sheet/strand, coil).

Main Results:

• Over 80% of human proteins in disordered protein databases contain one or more ARs.
• AR content decreases as protein disorder decreases.
• ARs constitute approximately 8% of a protein sequence and are, on average, 8 residues long.
• AR sequences exhibit high complexity and rarely overlap with LCRs.
• AR sequences demonstrate mixed conformational adaptability, favoring α-helix, β-sheet/strand, and coil structures.

Conclusions:

• Amyloidogenic regions are a significant feature of intrinsically disordered human proteins.
• The distinct sequence complexity and conformational adaptability of ARs contribute to their role in protein aggregation.
• These findings provide insights into the structural basis of amyloid formation in disordered proteins.