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

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.

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Luebben, A. V., Author
Bender, D., Author
Becker, S.1, Author              
Crowther, L. M., Author
Erven, I., Author
Hofmann, K., Author
Söding, J.2, Author              
Klemp, H., Author
Bellotti, C., Author
Stäuble, A., Author
Qiu, T., Author
Kathayat, R. S., Author
Dickinson, B. C., Author
Gärtner, J., Author
Sheldrick, G. M., Author
Krätzner, R., Author
Steinfeld, R., Author
Affiliations:
1Department of NMR Based Structural Biology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society, ou_3350124              
2Research Group of Quantitative and Computational Biology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society, ou_3350226              

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 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.

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Language(s): eng - English
 Dates: 2021-06-072022-03-012022-04-152022-04-15
 Publication Status: Published in print
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 Rev. Type: Peer
 Identifiers: DOI: 10.1126/sciadv.abj8633
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Title: Science Advances
Source Genre: Journal
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Pages: 9 Volume / Issue: 8 (15) Sequence Number: eabj8633 Start / End Page: - Identifier: -