Prolyl Endopeptidase-Like Facilitates the α-Synuclein Aggregation Seeding, and This Effect Is Reverted by Serine Peptidase Inhibitor PMSF

Santos, Gabriel S.; Oyadomari, William Y.; Carvalho, Elizangela A.; Torquato, Ricardo S.; Oliveira, Vitor

doi:10.3390/biom10060962

Cited by 4 publications

(4 citation statements)

References 58 publications

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“…Recently, Santos et al. also revealed that PREPL facilitates α-synuclein aggregation through a non-hydrolytic mechanism similar to that observed for PREP ( Santos et al., 2020 ). The relatively low activity of PREPL toward the ester substrates in vitro fits such a model.…”

Section: Discussionmentioning

confidence: 54%

Prolyl endopeptidase-like is a (thio)esterase involved in mitochondrial respiratory chain function

et al. 2021

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Summary Deficiency of the serine hydrolase prolyl endopeptidase-like (PREPL) causes a recessive metabolic disorder characterized by neonatal hypotonia, feeding difficulties, and growth hormone deficiency. The pathophysiology of PREPL deficiency and the physiological substrates of PREPL remain largely unknown. In this study, we connect PREPL with mitochondrial gene expression and oxidative phosphorylation by analyzing its protein interactors. We demonstrate that the long PREPL L isoform localizes to mitochondria, whereas PREPL S remains cytosolic. Prepl KO mice showed reduced mitochondrial complex activities and disrupted mitochondrial gene expression. Furthermore, mitochondrial ultrastructure was abnormal in a PREPL-deficient patient and Prepl KO mice. In addition, we reveal that PREPL has (thio)esterase activity and inhibition of PREPL by Palmostatin M suggests a depalmitoylating function. We subsequently determined the crystal structure of PREPL, thereby providing insight into the mechanism of action. Taken together, PREPL is a (thio)esterase rather than a peptidase and PREPL L is involved in mitochondrial homeostasis.

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Section: Discussionmentioning

confidence: 54%

Prolyl endopeptidase-like is a (thio)esterase involved in mitochondrial respiratory chain function

et al. 2021

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“…Recent findings suggest that protein-protein interactions are pivotal for the function of PREPL and that some of these interactions are independent of catalytic activity (15,19,20). Therefore, we evaluated if the CMS22 patient mutations have an effect on the interactome of PREPL.…”

Section: ) Patient Mutations In Prepl Disrupt Protein-protein Interac...mentioning

confidence: 99%

“…This phenotype was rescued with a catalytically inactive PREPL p.Ser559Ala variant, suggesting a catalytic independent mechanism. Moreover, PREPL interacts with α-synuclein, thereby influencing aggregation, without α-synuclein cleavage (20). For PREP, a homologue of PREPL, substrate binding in the catalytic site is thought to result in an allosteric change that alters protein-protein interactions (21).…”

Section: Introductionmentioning

confidence: 99%

Missense mutations in CMS22 patients reveal that PREPL has both enzymatic and non-enzymatic functions

Monnens,

Theodoropoulou,

Rosier

et al. 2023

Preprint

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Congenital myasthenic syndrome-22 (CMS22) is a rare genetic disorder caused by mutations in the prolyl endopeptidase-like (PREPL) gene. Since previous reports only described patients with deletions and nonsense mutations inPREPL, nothing is known about the effect of missense mutations in the pathology of CMS22. In this study, we have characterized missense mutations inPREPLin three CMS22 patients, all with hallmark phenotypes. Biochemical evaluation revealed that these missense mutations do not impair hydrolase activity, thereby challenging the conventional diagnostic criteria. Structural analysis shows that the mutations 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 show that CMS22 can be caused not only by deletion and truncation of PREPL but also by missense mutations that do not necessarily result in a loss of hydrolytic activity of PREPL.Graphical abstract

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“…The biological functions described in the section below include microbial invasion through the protective barrier, pathophysiology of human diseases, and plant nutrient uptake/mobilization, growth, and development. Apart from proteolysis, PPCEs can affect the biological system through protein–protein interactions (PPIs), such as the acceleration of α-synuclein aggregation that can lead to Parkinson’s disease [ 8 ]. Hence, studies of PPCEs are important for the pharmaceutical industries.…”

Section: Introductionmentioning

confidence: 99%

Post-Proline Cleaving Enzymes (PPCEs): Classification, Structure, Molecular Properties, and Applications

Baharin

Ting

Goh

2022

Plants

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Proteases or peptidases are hydrolases that catalyze the breakdown of polypeptide chains into smaller peptide subunits. Proteases exist in all life forms, including archaea, bacteria, protozoa, insects, animals, and plants due to their vital functions in cellular processing and regulation. There are several classes of proteases in the MEROPS database based on their catalytic mechanisms. This review focuses on post-proline cleaving enzymes (PPCEs) from different peptidase families, as well as prolyl endoprotease/oligopeptidase (PEP/POP) from the serine peptidase family. To date, most PPCEs studied are of microbial and animal origins. Recently, there have been reports of plant PPCEs. The most common PEP/POP are members of the S9 family that comprise two conserved domains. The substrate-limiting β-propeller domain prevents unwanted digestion, while the α/β hydrolase catalyzes the reaction at the carboxyl-terminal of proline residues. PPCEs display preferences towards the Pro-X bonds for hydrolysis. This level of selectivity is substantial and has benefited the brewing industry, therapeutics for celiac disease by targeting proline-rich substrates, drug targets for human diseases, and proteomics analysis. Protein engineering via mutagenesis has been performed to improve heat resistance, pepsin-resistant capability, specificity, and protein turnover of PPCEs for pharmacological applications. This review aims to synthesize recent structure–function studies of PPCEs from different families of peptidases to provide insights into the molecular mechanism of prolyl cleaving activity. Despite the non-exhaustive list of PPCEs, this is the first comprehensive review to cover the biochemical properties, biological functions, and biotechnological applications of PPCEs from the diverse taxa.

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Prolyl Endopeptidase-Like Facilitates the α-Synuclein Aggregation Seeding, and This Effect Is Reverted by Serine Peptidase Inhibitor PMSF

Cited by 4 publications

References 58 publications

Prolyl endopeptidase-like is a (thio)esterase involved in mitochondrial respiratory chain function

Prolyl endopeptidase-like is a (thio)esterase involved in mitochondrial respiratory chain function

Missense mutations in CMS22 patients reveal that PREPL has both enzymatic and non-enzymatic functions

Post-Proline Cleaving Enzymes (PPCEs): Classification, Structure, Molecular Properties, and Applications

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