Cln5 represents a new type of cysteine-based S -depalmitoylase linked to neurodegeneration
2022 | journal article; research paper. A publication with affiliation to the University of Göttingen.
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- Authors
- Luebben, Anna V.; Bender, Daniel; Becker, Stefan; Crowther, Lisa M.; Erven, Ilka; Hofmann, Kay; Söding, Johannes ; Klemp, Henry; Bellotti, Cristina; Stäuble, Andreas; Steinfeld, Robert
- Abstract
- 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. Cln5 structure reveals thioesterase activity among N1pC/P60 proteins, stressing the role of S -depalmitoylation in neurodegeneration.
- Issue Date
- 2022
- Journal
- Science Advances
- Project
- EXC 2067: Multiscale Bioimaging
- Working Group
- RG Gärtner
RG Söding (Quantitative and Computational Biology) - eISSN
- 2375-2548
- Language
- English