Universität zu Köln

Luebben, Anna, V, Bender, Daniel ORCID: 0000-0002-2975-4186, Becker, Stefan, Crowther, Lisa M., Erven, Ilka ORCID: 0000-0002-1095-6861, Hofmann, Kay, Soeding, Johannes, Klemp, Henry ORCID: 0000-0002-3147-3017, Bellotti, Cristina ORCID: 0000-0002-3999-2807, Stauble, Andreas, Qiu, Tian, Kathayat, Rahul S., Dickinson, Bryan C., Gaertner, Jutta, Sheldrick, George M., Kraetzner, Ralph and Steinfeld, Robert (2022). Cln5 represents a new type of cysteine-based S-depalmitoylase linked to neurodegeneration. Sci. Adv., 8 (15). WASHINGTON: AMER ASSOC ADVANCEMENT SCIENCE. ISSN 2375-2548

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Luebben, Anna, V UNSPECIFIED UNSPECIFIED UNSPECIFIED Bender, Daniel UNSPECIFIED orcid.org/0000-0002-2975-4186 UNSPECIFIED Becker, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED Crowther, Lisa M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Erven, Ilka UNSPECIFIED orcid.org/0000-0002-1095-6861 UNSPECIFIED Hofmann, Kay UNSPECIFIED UNSPECIFIED UNSPECIFIED Soeding, Johannes UNSPECIFIED UNSPECIFIED UNSPECIFIED Klemp, Henry UNSPECIFIED orcid.org/0000-0002-3147-3017 UNSPECIFIED Bellotti, Cristina UNSPECIFIED orcid.org/0000-0002-3999-2807 UNSPECIFIED Stauble, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED Qiu, Tian UNSPECIFIED UNSPECIFIED UNSPECIFIED Kathayat, Rahul S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Dickinson, Bryan C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gaertner, Jutta UNSPECIFIED UNSPECIFIED UNSPECIFIED Sheldrick, George M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kraetzner, Ralph UNSPECIFIED UNSPECIFIED UNSPECIFIED Steinfeld, Robert UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-683438
DOI:	10.1126/sciadv.abj8633
Journal or Publication Title:	Sci. Adv.
Volume:	8
Number:	15
Date:	2022
Publisher:	AMER ASSOC ADVANCEMENT SCIENCE
Place of Publication:	WASHINGTON
ISSN:	2375-2548
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PALMITOYL-PROTEIN THIOESTERASE; ISOPEPTIDASE; MUTATIONS; MODEL; VALIDATION; PHYSIOLOGY; SERVER Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/68343