7obm
From Proteopedia
Crystal structure of the human Prolyl Endopeptidase-Like protein short form (residues 90-727)
Structural highlights
Disease[PPCEL_HUMAN] 2p21 microdeletion syndrome;Atypical hypotonia-cystinuria syndrome;2p21 microdeletion syndrome without cystinuria;Hypotonia-cystinuria syndrome. The gene represented in this entry is involved in disease pathogenesis. Hypotonia-cystinuria syndrome is a contiguous gene syndrome caused by a homozygous deletion on chromosome 2p21 that disrupts the gene represented in this entry and SLC3A1 (PubMed:16385448, PubMed:21686663). A homozygous 77.4-kb deletion that disrupts the gene represented in this entry, SLC3A1 and CAMKMT, causes atypical hypotonia-cystinuria syndrome, characterized by mild to moderate mental retardation and respiratory chain complex IV deficiency (PubMed:21686663). Patient cells exhibit a larger trans-Golgi network and a reduced redistribution of AP-1 complex, which causes impairment in AP-1 mediated membrane-cytoplasm recycling and secretion (PubMed:23321636).[1] [2] [3] The disease is caused by variants affecting the gene represented in this entry. Function[PPCEL_HUMAN] Serine peptidase whose precise substrate specificity remains unclear (PubMed:16143824, PubMed:16385448, PubMed:28726805). Does not cleave peptides after a arginine or lysine residue (PubMed:16143824). Regulates trans-Golgi network morphology and sorting by regulating the membrane binding of the AP-1 complex (PubMed:23321636). May play a role in the regulation of synaptic vesicle exocytosis (PubMed:24610330).[4] [5] [6] [7] [8] Publication Abstract from PubMedDeficiency 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 PREPLL isoform localizes to mitochondria, whereas PREPLS 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 PREPLL is involved in mitochondrial homeostasis. Prolyl endopeptidase-like is a (thio)esterase involved in mitochondrial respiratory chain function.,Rosier K, McDevitt MT, Smet J, Floyd BJ, Verschoore M, Marcaida MJ, Bingman CA, Lemmens I, Dal Peraro M, Tavernier J, Cravatt BF, Gounko NV, Vints K, Monnens Y, Bhalla K, Aerts L, Rashan EH, Vanlander AV, Van Coster R, Regal L, Pagliarini DJ, Creemers JWM iScience. 2021 Nov 14;24(12):103460. doi: 10.1016/j.isci.2021.103460. eCollection, 2021 Dec 17. PMID:34888501[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Large Structures | Bingman, C A | Brendan, J F | Creemers, J W.M | MPP, Mitochondrial Protein Partnership | Marcaida, M J | McDevitt, M T | Pagliarini, D J | Rosier, K | Smith, R W | Esterase mitochondrial beta-propeller | Hydrolase | Mitochondrial protein partnership | Mpp | PSI, Protein structure initiative | Structural genomic
