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Journal Article

Cln5 represents a new type of cysteine-basedS-depalmitoylase linked to neurodegeneration

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Becker,  S.
Department of NMR Based Structural Biology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Söding,  J.
Research Group of Quantitative and Computational Biology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Citation

Luebben, A. V., Bender, D., Becker, S., Crowther, L. M., Erven, I., Hofmann, K., et al. (2022). Cln5 represents a new type of cysteine-basedS-depalmitoylase linked to neurodegeneration. Science Advances, 8(15): eabj8633. doi:10.1126/sciadv.abj8633.


Cite as: https://hdl.handle.net/21.11116/0000-000A-7786-9
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.