7obm

From Proteopedia

(Difference between revisions)

Revision as of 07:13, 2 February 2022

Crystal structure of the human Prolyl Endopeptidase-Like protein short form (residues 90-727)

Structural highlights

7obm is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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 PubMed

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 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.

References

↑ Jaeken J, Martens K, Francois I, Eyskens F, Lecointre C, Derua R, Meulemans S, Slootstra JW, Waelkens E, de Zegher F, Creemers JW, Matthijs G. Deletion of PREPL, a gene encoding a putative serine oligopeptidase, in patients with hypotonia-cystinuria syndrome. Am J Hum Genet. 2006 Jan;78(1):38-51. Epub 2005 Nov 23. PMID:16385448 doi:http://dx.doi.org/S0002-9297(07)60804-0
↑ Chabrol B, Martens K, Meulemans S, Cano A, Jaeken J, Matthijs G, Creemers JW. Deletion of C2orf34, PREPL and SLC3A1 causes atypical hypotonia-cystinuria syndrome. BMJ Case Rep. 2009;2009. pii: bcr08.2008.0719. doi: 10.1136/bcr.08.2008.0719., Epub 2009 Feb 2. PMID:21686663 doi:http://dx.doi.org/10.1136/bcr.08.2008.0719
↑ Radhakrishnan K, Baltes J, Creemers JW, Schu P. Trans-Golgi network morphology and sorting is regulated by prolyl-oligopeptidase-like protein PREPL and the AP-1 complex subunit mu1A. J Cell Sci. 2013 Mar 1;126(Pt 5):1155-63. doi: 10.1242/jcs.116079. Epub 2013 Jan , 15. PMID:23321636 doi:http://dx.doi.org/10.1242/jcs.116079
↑ Szeltner Z, Alshafee I, Juhasz T, Parvari R, Polgar L. The PREPL A protein, a new member of the prolyl oligopeptidase family, lacking catalytic activity. Cell Mol Life Sci. 2005 Oct;62(19-20):2376-81. PMID:16143824 doi:http://dx.doi.org/10.1007/s00018-005-5262-5
↑ Jaeken J, Martens K, Francois I, Eyskens F, Lecointre C, Derua R, Meulemans S, Slootstra JW, Waelkens E, de Zegher F, Creemers JW, Matthijs G. Deletion of PREPL, a gene encoding a putative serine oligopeptidase, in patients with hypotonia-cystinuria syndrome. Am J Hum Genet. 2006 Jan;78(1):38-51. Epub 2005 Nov 23. PMID:16385448 doi:http://dx.doi.org/S0002-9297(07)60804-0
↑ Radhakrishnan K, Baltes J, Creemers JW, Schu P. Trans-Golgi network morphology and sorting is regulated by prolyl-oligopeptidase-like protein PREPL and the AP-1 complex subunit mu1A. J Cell Sci. 2013 Mar 1;126(Pt 5):1155-63. doi: 10.1242/jcs.116079. Epub 2013 Jan , 15. PMID:23321636 doi:http://dx.doi.org/10.1242/jcs.116079
↑ Regal L, Shen XM, Selcen D, Verhille C, Meulemans S, Creemers JW, Engel AG. PREPL deficiency with or without cystinuria causes a novel myasthenic syndrome. Neurology. 2014 Apr 8;82(14):1254-60. doi: 10.1212/WNL.0000000000000295. Epub, 2014 Mar 7. PMID:24610330 doi:http://dx.doi.org/10.1212/WNL.0000000000000295
↑ Regal L, Martensson E, Maystadt I, Voermans N, Lederer D, Burlina A, Juan Fita MJ, Hoogeboom AJM, Olsson Engman M, Hollemans T, Schouten M, Meulemans S, Jonson T, Francois I, Gil Ortega D, Kamsteeg EJ, Creemers JWM. PREPL deficiency: delineation of the phenotype and development of a functional blood assay. Genet Med. 2018 Jan;20(1):109-118. doi: 10.1038/gim.2017.74. Epub 2017 Jul 20. PMID:28726805 doi:http://dx.doi.org/10.1038/gim.2017.74
↑ 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. Prolyl endopeptidase-like is a (thio)esterase involved in mitochondrial respiratory chain function. iScience. 2021 Nov 14;24(12):103460. doi: 10.1016/j.isci.2021.103460. eCollection, 2021 Dec 17. PMID:34888501 doi:http://dx.doi.org/10.1016/j.isci.2021.103460

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7obm"

@@ Line 1: / Line 1: @@
 ==Crystal structure of the human Prolyl Endopeptidase-Like protein short form (residues 90-727)==
-<StructureSection load='7obm' size='340' side='right'caption='[[7obm]]' scene=''>
+<StructureSection load='7obm' size='340' side='right'caption='[[7obm]], [[Resolution|resolution]] 3.10&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7OBM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7OBM FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7obm]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7OBM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7OBM FirstGlance]. <br>
 </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7obm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7obm OCA], [https://pdbe.org/7obm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7obm RCSB], [https://www.ebi.ac.uk/pdbsum/7obm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7obm ProSAT]</span></td></tr>
 </table>
+== Disease ==
+[[https://www.uniprot.org/uniprot/PPCEL_HUMAN 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).<ref>PMID:16385448</ref> <ref>PMID:21686663</ref> <ref>PMID:23321636</ref>   The disease is caused by variants affecting the gene represented in this entry.
+== Function ==
+[[https://www.uniprot.org/uniprot/PPCEL_HUMAN 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).<ref>PMID:16143824</ref> <ref>PMID:16385448</ref> <ref>PMID:23321636</ref> <ref>PMID:24610330</ref> <ref>PMID:28726805</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+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 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<ref>PMID:34888501</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 7obm" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Prolyl Endopeptidase|Prolyl Endopeptidase]]
+== References ==
+<references/>
 __TOC__
 </StructureSection>
 [[Category: Large Structures]]
-[[Category: Bingman CA]]
+[[Category: Bingman, C A]]
-[[Category: Brendan JF]]
+[[Category: Brendan, J F]]
-[[Category: Creemers JWM]]
+[[Category: Creemers, J W.M]]
-[[Category: Marcaida MJ]]
+[[Category: MPP, Mitochondrial Protein Partnership]]
-[[Category: McDevitt MT]]
+[[Category: Marcaida, M J]]
-[[Category: Pagliarini DJ]]
+[[Category: McDevitt, M T]]
-[[Category: Rosier K]]
+[[Category: Pagliarini, D J]]
-[[Category: Smith RW]]
+[[Category: Rosier, K]]
+[[Category: Smith, R W]]
+[[Category: Esterase mitochondrial beta-propeller]]
+[[Category: Hydrolase]]
+[[Category: Mitochondrial protein partnership]]
+[[Category: Mpp]]
+[[Category: PSI, Protein structure initiative]]
+[[Category: Structural genomic]]

7obm

From Proteopedia

Revision as of 07:13, 2 February 2022

Crystal structure of the human Prolyl Endopeptidase-Like protein short form (residues 90-727)

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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