Second Sphere Interactions in Amyloidogenic Diseases

Area of Science:

• Biochemistry
• Molecular Biology
• Pathology

Background:

• Amyloids are pathogenic protein aggregates with a cross β structure, central to organ dysfunction in amyloidogenic diseases.
• Protein aggregation is triggered by conformational changes influenced by factors like metal binding, mutations, and post-translational modifications.
• Misfolded/unfolded proteins and peptides are implicated in various neurodegenerative and metabolic diseases.

Purpose of the Study:

• To review the role of second sphere modifications in amyloidogenic diseases.
• To discuss how second sphere effects alter protein structure, reactivity, and cytotoxicity.
• To explore the link between second sphere effects and the etiopathology of diseases such as Alzheimer's, T2DM, Parkinson's, Huntington's, and prion diseases.

Main Methods:

• Review of existing literature on amyloidogenic proteins and peptides.
• Analysis of the impact of amino acid residues in the second coordination sphere of active sites.
• Examination of changes in H-bonding patterns and protein-protein interactions.

Main Results:

• Second sphere effects significantly alter protein structure and reactivity.
• These effects influence transition metal binding and cofactor interactions, crucial in disease pathology.
• Second sphere modifications impact redox reaction mechanisms and contribute to oxidative damage.

Conclusions:

• Second sphere modifications are critical determinants in the pathogenesis of amyloidogenic diseases.
• Understanding these effects provides insights into the molecular mechanisms underlying Alzheimer's, T2DM, Parkinson's, Huntington's, and prion diseases.
• Targeting second sphere interactions may offer novel therapeutic strategies for amyloidogenic diseases.