Fibril modelling by sequence and structure conservation analysis combined with protein docking techniques:...

Area of Science:

• Biochemistry
• Structural Biology
• Biophysics

Background:

• Amyloid fibrils are protein aggregates implicated in diseases.
• Atomic resolution structures of amyloid fibrils are difficult to obtain.
• Understanding protein domain destabilization is key to amyloid formation.

Purpose of the Study:

• To identify unstable segments within the beta(2)-microglobulin (beta(2)-m) domain.
• To correlate protein conservation with local stability.
• To propose a structural model for beta(2)-m amyloid fibrils.

Main Methods:

• Extensive sequence and structure conservation analysis of the beta(2)-m domain.
• Utilized a dataset of 51 high-resolution C1 set domain structures.
• Incorporated 132 clustered PSI-BLAST search results.
• Reviewed experimental data from urea denaturation, proteolysis, and H/D exchange.

Main Results:

• Strands A, D, and G of beta(2)-m were identified as less conserved and stable.
• Strands B, C, E, and F were found to be conserved and stable.
• A structural model for the polymerized unit of beta(2)-m was proposed.
• A fibril model consistent with cross-beta structure was suggested.

Conclusions:

• Less conserved segments of beta(2)-m are crucial for amyloidogenic transformation.
• Conservation analysis provides insights into protein stability and amyloid formation.
• The proposed model aids in understanding beta(2)-m fibril structure and mechanism.