@article{TEXTUAL,
      recid = {10913},
      author = {Luebben, Anna V. and Bender, Daniel and Becker, Stefan and  Crowther, Lisa M. and Erven, Ilka and Hofmann, Kay and  Söding, Johannes and Klemp, Henry and Bellotti, Cristina  and Stäuble, Andreas and Qiu, Tian and Kathayat, Rahul S.  and Dickinson, Bryan C. and Gärtner, Jutta and Sheldrick,  George M. and Krätzner, Ralph and Steinfeld, Robert},
      title = {Cln5 represents a new type of cysteine-based  S-depalmitoylase linked to neurodegeneration},
      journal = {Science Advances},
      address = {2022-04-15},
      number = {TEXTUAL},
      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.},
      url = {http://knowledge.uchicago.edu/record/10913},
}