8RFB

Cryo-EM structure of the R243C mutant of human Prolyl Endopeptidase-Like (PREPL) protein involved in Congenital myasthenic syndrome-22 (CMS22)

Summary for 8RFB

• Entry DOI: 10.2210/pdb8rfb/pdb
• Related: 7OBM
• EMDB information: 19117
• Descriptor: Prolyl endopeptidase-like (1 entity in total)
• Functional Keywords: thio-esterase, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 73477.40

Authors

Theodoropoulou, A.,Cavani, E.,Antanasijevic, A.,Marcaida, M.J.,Dal Peraro, M. (deposition date: 2023-12-12, release date: 2024-09-04, Last modification date: 2024-10-09)

Primary citation

Monnens, Y.,Theodoropoulou, A.,Rosier, K.,Bhalla, K.,Mahy, A.,Vanhoutte, R.,Meulemans, S.,Cavani, E.,Antanasijevic, A.,Lemmens, I.,Lee, J.A.,Spellicy, C.J.,Schroer, R.J.,Maselli, R.A.,Laverty, C.G.,Agostinis, P.,Pagliarini, D.J.,Verhelst, S.,Marcaida, M.J.,Rochtus, A.,Dal Peraro, M.,Creemers, J.W.
Missense variants in CMS22 patients reveal that PREPL has both enzymatic and nonenzymatic functions.
JCI Insight, 9:-, 2024

PubMed Abstract: Congenital myasthenic syndrome-22 (CMS22, OMIM 616224) is a rare genetic disorder caused by deleterious genetic variation in the prolyl endopeptidase-like (PREPL) gene. Previous reports have described patients with deletions and nonsense variants in PREPL, but nothing is known about the effect of missense variants in the pathology of CMS22. In this study, we have functionally characterized missense variants in PREPL from three CMS22 patients, all with hallmark phenotypes. Biochemical evaluation revealed that these missense variants do not impair hydrolase activity, thereby challenging the conventional diagnostic criteria and disease mechanism. Structural analysis showed that the variants affect regions most likely involved in intra-protein or protein-protein interactions. Indeed, binding to a selected group of known interactors was differentially reduced for the three mutants. The importance of non-hydrolytic functions of PREPL was investigated in catalytically inactive PREPL p.Ser559Ala cell lines which showed that hydrolytic activity of PREPL is needed for normal mitochondrial function but not for regulating AP1-mediated transport in the trans-Golgi network. In conclusion, these studies showed that CMS22 can be caused not only by deletion and truncation of PREPL but also by missense variants that do not necessarily result in a loss of hydrolytic activity of PREPL.

PubMed: 39078710
DOI: 10.1172/jci.insight.179276

Experimental method

ELECTRON MICROSCOPY (4.01 Å)