Flanking regions, amyloid cores, and polymorphism: the potential interplay underlying structural diversity

Area of Science:

• Biochemistry
• Neuroscience
• Structural Biology

Background:

• Amyloid cores, rich in β-sheets, define protein aggregates in neurodegenerative diseases.
• The same protein sequence can form diverse amyloid structures (polymorphs).
• These structural variants are linked to distinct disease pathologies and phenotypes.

Purpose of the Study:

• To review the role of flanking regions in inducing amyloid polymorphism.
• To explore how flanking regions' disordered nature contributes to conformational diversity.
• To identify potential therapeutic strategies targeting these regions.

Main Methods:

• Literature review focusing on amyloid polymorphism.
• Analysis of flanking regions in well-characterized proteins (amyloid-β, α-synuclein, Tau, TDP-43).
• Discussion of factors influencing aggregate structure.

Main Results:

• Flanking regions adjacent to amyloid cores are often disordered.
• This disorder provides functional promiscuity, enabling conformational polymorphism.
• Polymorphism in amyloid-β, α-synuclein, Tau, and TDP-43 is influenced by these regions.

Conclusions:

• Flanking regions are key players in the generation of amyloid polymorphs.
• Understanding these regions is crucial for developing targeted therapies.
• Modulating flanking region properties offers a novel therapeutic avenue for neurodegenerative disorders.