Exploring the 'aggregation-prone' core of human Cystatin C: A structural study

Area of Science:

• Protein aggregation
• Amyloid formation
• Molecular biology

Background:

• Human Cystatin C (hCC) is a cysteine protease inhibitor.
• Oligomerization of hCC is implicated in Icelandic hereditary cerebral amyloid angiopathy.
• Previous work identified the LQVVR peptide from hCC as amyloidogenic.

Purpose of the Study:

• To identify the shortest peptide sequences responsible for hCC fibril formation.
• To experimentally validate predictions from the AMYLPRED algorithm.

Main Methods:

• Peptide synthesis and in vitro self-assembly studies.
• Electron microscopy and X-ray fiber diffraction for structural analysis.
• ATR FT-IR spectroscopy and Congo red staining for fibril characterization.

Main Results:

• Three distinct hCC-derived peptides were synthesized and shown to self-assemble into amyloid-like fibrils.
• Structural analyses confirmed the fibrillar nature of the self-assembled peptides.
• All studied peptides contribute to the aggregation-prone core of hCC.

Conclusions:

• Specific short peptide stretches within hCC are sufficient to drive amyloid fibril formation.
• These peptides represent critical components of the aggregation-prone core of hCC.
• The findings advance the understanding of hCC-related amyloidosis.