| Autor: |
Luebben, A., Bender, D., Becker, S., Crowther, L., Erven, I., Hofmann, K., Söding, J., Klemp, H., Bellotti, C., Stäuble, A., Qiu, T., Kathayat, R., Dickinson, B., Gärtner, J., Sheldrick, G., Krätzner, R., Steinfeld, R. |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Zdroj: |
Science Advances |
| Popis: |
Genetic CLN5 variants are associated with childhood neurodegeneration and Alzheimer’s disease; however, the molecular function of ceroid lipofuscinosis neuronal protein 5 (Cln5) is unknown. We solved the Cln5 crystal structure and identified a region homologous to the catalytic domain of members of the N1pC/P60 superfamily of papain-like enzymes. However, we observed no protease activity for Cln5; and instead, we discovered that Cln5 and structurally related PPPDE1 and PPPDE2 have efficient cysteine palmitoyl thioesterase (S-depalmitoylation) activity using fluorescent substrates. Mutational analysis revealed that the predicted catalytic residues histidine-166 and cysteine-280 are critical for Cln5 thioesterase activity, uncovering a new cysteine-based catalytic mechanism for S-depalmitoylation enzymes. Last, we found that Cln5-deficient neuronal progenitor cells showed reduced thioesterase activity, confirming live cell function of Cln5 in setting S-depalmitoylation levels. Our results provide new insight into the function of Cln5, emphasize the importance of S-depalmitoylation in neuronal homeostasis, and disclose a new, unexpected enzymatic function for the N1pC/P60 superfamily of proteins. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
|
