Domain swapping in N-truncated human cystatin C

Area of Science:

• Biochemistry
• Structural Biology
• Neuroscience

Background:

• Human cystatin C (HCC) is a protease inhibitor found in body fluids, notably cerebrospinal fluid.
• Oligomerization of HCC can lead to amyloid deposits, causing amyloidosis, especially with the Leu68Gln variant.
• N-terminally truncated HCC (THCC) is the predominant form in amyloid deposits, likely due to proteolytic activity in cerebrospinal fluid.

Purpose of the Study:

• To determine the crystal structure of N-truncated human cystatin C (THCC).
• To investigate the mechanism of dimerization and oligomerization of THCC in amyloid deposits.
• To compare the structural features of THCC dimers with those of full-length HCC.

Main Methods:

• X-ray crystallography to determine the 3D structure of N-truncated HCC.
• Analysis of protein quaternary structure and intermolecular interactions.
• Comparison of structural data with full-length HCC.

Main Results:

• The crystal structure of THCC reveals dimerization through 3D domain swapping, similar to full-length HCC.
• THCC dimers exhibit structural variability and form closed octameric assemblies.
• These octamers are structurally identical to those formed by full-length HCC, involving intermolecular beta-sheet formation.

Conclusions:

• 3D domain swapping is a conserved mechanism for HCC oligomerization, leading to amyloid formation.
• The structural flexibility of THCC dimers contributes to the formation of stable octameric assemblies.
• Understanding THCC structure provides insights into the molecular basis of cystatin C-related amyloidosis.