6R99

Crystal Structure of Human CLN protein 5 (Ceroid Lipofuscinosis Neuronal Protein 5)

Summary for 6R99

• Entry DOI: 10.2210/pdb6r99/pdb
• Descriptor: Ceroid-lipofuscinosis neuronal protein 5, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• Functional Keywords: neuronal ceroid lipofiscinosis, cln5, circularly-permuted papain-like fold, glycoprotein, unknown function
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 48359.10

Authors

Luebben, A.V.,Sheldrick, G.M. (deposition date: 2019-04-03, release date: 2020-04-22, Last modification date: 2022-09-28)

Primary citation

Luebben, A.V.,Bender, D.,Becker, S.,Crowther, L.M.,Erven, I.,Hofmann, K.,Soding, J.,Klemp, H.,Bellotti, C.,Stauble, A.,Qiu, T.,Kathayat, R.S.,Dickinson, B.C.,Gartner, J.,Sheldrick, G.M.,Kratzner, R.,Steinfeld, R.
Cln5 represents a new type of cysteine-based S -depalmitoylase linked to neurodegeneration.
Sci Adv, 8:eabj8633-eabj8633, 2022

PubMed Abstract: Genetic 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 (-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 -depalmitoylation enzymes. Last, we found that Cln5-deficient neuronal progenitor cells showed reduced thioesterase activity, confirming live cell function of Cln5 in setting -depalmitoylation levels. Our results provide new insight into the function of Cln5, emphasize the importance of -depalmitoylation in neuronal homeostasis, and disclose a new, unexpected enzymatic function for the N1pC/P60 superfamily of proteins.

PubMed: 35427157
DOI: 10.1126/sciadv.abj8633

Experimental method

X-RAY DIFFRACTION (2.7 Å)