Research On The Structural Stability Of Cystatin C And Interaction Between Cystatin C And Amyloid β-Protein

The formation and deposition of amyloid fibrils have been linked to about 30 important human degenerative diseases, including transmissible spongiform encephalopathy(TSE), systemic amyloidosis ,Alzheimer’s disease and Parkinson’s disease. Investigations for the mechanism by which amyloid forms are urgently needed with more attentions of the amyloid fibrils disease. Human cystatin C (HCC) has been reported to colocalize with amyloid plaque of Alzheimer’s disease and Down’s syndrome. The L68Q variant of HCC is the causative agent of HCCAA. Cystatin C binds amyloid-β(Aβ) and inhibits formation of Aβfibrils and oligomers both in vitro and in mouse models of amyloid deposition. The differences between HCC and its mutant of their structural stability are still unclear. The interaction of HCC binding with Aβhas been poorly understood.In this study, we investigated the structure changes of the L68Q mutant compared with wild-type HCC using molecular dynamic simulations at 328k. Our results suggested that the L68Q mutant exhibited larger secondary structural fluctuations and hydrophobic core expanding tendency compared with the wild-type HCC. More importantly, the appendant structure is a key area in L68Q. The process of HCC formed dimers may be that AS region flip to the molecular center and promote theβ1-α1-β2 region departure from the molecular center to form the substructure of the dimers. To obtain more information about the interaction of HCC binding with Aβ, we performed the docking calculations between HCC and Aβ. Using the complex structure which was accorded with the binding epitopes to perform molecular dynamic simulation. The results showed that HCC could bind toβ-sheet form of Aβbetter than itsα-helix form.This study can provide a foundation to find the potential target and screen the effective drugs.