Coiled-coil stutter and link segments in keratin and other intermediate filament molecules: a computer modeling study

Area of Science:

• Structural biology
• Biochemistry
• Molecular modeling

Background:

• Intermediate filaments (IFs) are crucial cytoskeletal proteins with a coiled-coil rod domain structure.
• Four specific regions with structural discontinuities have been identified within IF coiled-coil domains.
• These discontinuities include a phase shift in heptad periodicity and three links lacking heptad substructure.

Purpose of the Study:

• To investigate the structural and conformational implications of discontinuities in IF coiled-coil rod domains.
• To analyze the sequence and structural variations in specific link regions (L1, L2, L12).
• To understand the role of charge variations and ionic interactions in IF assembly.

Main Methods:

• Computer-based molecular modeling was employed to study the identified structural regions.
• Comparative sequence analysis was performed across different types of IF molecules.
• Conformational analysis of alpha-helical coiled-coils and non-coiled-coil linkers was conducted.

Main Results:

• The phase shift in heptad periodicity is accommodated without significant distortion of the double-helical conformation.
• The L2 link exhibits a conserved, tightly wrapped conformation across IF types.
• L12 links show sequence similarities suggesting partial beta structure, while L1 links display diverse structures and lengths.
• Variations in link charges indicate a potential role for ionic interactions in filament assembly.

Conclusions:

• The structural discontinuities within IF coiled-coil domains are conformationally manageable.
• Specific link regions (L2, L12, L1) possess distinct structural characteristics and variations.
• Ionic interactions likely contribute significantly to the assembly of intermediate filaments.
• Findings have broader implications for understanding alpha-fibrous proteins with similar structural features.