Lecture: Modulation of the stability of cystatin C by intra- and extramolecular factors

Prof. Aneta Szymańsk

Department of Biomedicinal Chemistry, Faculty of Chemistry, University of Gdańsk, Poland

28. 9. 2023 – 10:15 – B220

Human cystatin C (hCC) is associated with physiological and pathological processes in human organism. It functions mainly as an inhibitor of cysteine proteases, but also exhibits neurodegenerative and neuroprotective properties. The wild-type protein modulates the amyloid-β peptide oligomerization and toxicity, protecting at the same time neuron cells. The L68Q variant of hCC, on the other hand, is associated with severe state called hereditary cerebral amyloid angiopathy (HCAA), a disease resulting from the protein oligomerization, causing brain artery damage.
Oligomerization of hCC is a result of domain swapping. The protein conformational stability and unfolding necessary for the process to occur is partially controlled by the sequence of the L1 loop and hydrophobic interaction network, centered around leucine at position 68 located in the hydrophobic core of the protein. hCC oligomerization occurs spontaneously as a result of the above mentioned L68Q mutation or can be induced by external factors including temperature, pH changes or denaturation agents. Redox-active metal ions and biological membranes also play a vital role in the process.
Understanding the impact of intra- and intermolecular factors on hCC’s conformational stability and propensity for oligomerization provides insights into the mechanism underlying amyloidogenic protein folding and misfolding. It also is a starting point for a design of an effective treatment against HCAA.

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