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5lnf

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Revision as of 10:43, 12 August 2020

Solution NMR structure of farnesylated PEX19, C-terminal domain

Structural highlights

5lnf is a 1 chain structure with sequence from Human. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	PEX19, HK33, PXF, OK/SW-cl.22 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[PEX19_HUMAN] Defects in PEX19 are the cause of peroxisome biogenesis disorder complementation group 14 (PBD-CG14) [MIM:614886]; also known as PBD-CGJ. PBD refers to a group of peroxisomal disorders arising from a failure of protein import into the peroxisomal membrane or matrix. The PBD group is comprised of four disorders: Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and classical rhizomelic chondrodysplasia punctata (RCDP). ZWS, NALD and IRD are distinct from RCDP and constitute a clinical continuum of overlapping phenotypes known as the Zellweger spectrum. The PBD group is genetically heterogeneous with at least 14 distinct genetic groups as concluded from complementation studies.^[1] Defects in PEX19 are the cause of peroxisome biogenesis disorder 12A (PBD12A) [MIM:614886]. A fatal peroxisome biogenesis disorder belonging to the Zellweger disease spectrum and clinically characterized by severe neurologic dysfunction with profound psychomotor retardation, severe hypotonia and neonatal seizures, craniofacial abnormalities, liver dysfunction, and biochemically by the absence of peroxisomes. Additional features include cardiovascular and skeletal defects, renal cysts, ocular abnormalities, and hearing impairment. Most severely affected individuals with the classic form of the disease (classic Zellweger syndrome) die within the first year of life.

Function

[PEX19_HUMAN] Necessary for early peroxisomal biogenesis. Acts both as a cytosolic chaperone and as an import receptor for peroxisomal membrane proteins (PMPs). Binds and stabilizes newly synthesized PMPs in the cytoplasm by interacting with their hydrophobic membrane-spanning domains, and targets them to the peroxisome membrane by binding to the integral membrane protein PEX3. Excludes CDKN2A from the nucleus and prevents its interaction with MDM2, which results in active degradation of TP53.^[2] ^[3] ^[4] ^[5] ^[6] ^[7]

Publication Abstract from PubMed

The transport of peroxisomal membrane proteins (PMPs) requires the soluble PEX19 protein as chaperone and import receptor. Recognition of cargo PMPs by the C-terminal domain (CTD) of PEX19 is required for peroxisome biogenesis in vivo. Farnesylation at a C-terminal CaaX motif in PEX19 enhances the PMP interaction, but the underlying molecular mechanisms are unknown. Here, we report the NMR-derived structure of the farnesylated human PEX19 CTD, which reveals that the farnesyl moiety is buried in an internal hydrophobic cavity. This induces substantial conformational changes that allosterically reshape the PEX19 surface to form two hydrophobic pockets for the recognition of conserved aromatic/aliphatic side chains in PMPs. Mutations of PEX19 residues that either mediate farnesyl contacts or are directly involved in PMP recognition abolish cargo binding and cannot complement a DeltaPEX19 phenotype in human Zellweger patient fibroblasts. Our results demonstrate an allosteric mechanism for the modulation of protein function by farnesylation.

Allosteric modulation of peroxisomal membrane protein recognition by farnesylation of the peroxisomal import receptor PEX19.,Emmanouilidis L, Schutz U, Tripsianes K, Madl T, Radke J, Rucktaschel R, Wilmanns M, Schliebs W, Erdmann R, Sattler M Nat Commun. 2017 Mar 10;8:14635. doi: 10.1038/ncomms14635. PMID:28281558^[8]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Mohamed S, El-Meleagy E, Nasr A, Ebberink MS, Wanders RJ, Waterham HR. A mutation in PEX19 causes a severe clinical phenotype in a patient with peroxisomal biogenesis disorder. Am J Med Genet A. 2010 Sep;152A(9):2318-21. doi: 10.1002/ajmg.a.33560. PMID:20683989 doi:10.1002/ajmg.a.33560
↑ Matsuzono Y, Kinoshita N, Tamura S, Shimozawa N, Hamasaki M, Ghaedi K, Wanders RJ, Suzuki Y, Kondo N, Fujiki Y. Human PEX19: cDNA cloning by functional complementation, mutation analysis in a patient with Zellweger syndrome, and potential role in peroxisomal membrane assembly. Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):2116-21. PMID:10051604
↑ Sacksteder KA, Jones JM, South ST, Li X, Liu Y, Gould SJ. PEX19 binds multiple peroxisomal membrane proteins, is predominantly cytoplasmic, and is required for peroxisome membrane synthesis. J Cell Biol. 2000 Mar 6;148(5):931-44. PMID:10704444
↑ Sugihara T, Kaul SC, Kato J, Reddel RR, Nomura H, Wadhwa R. Pex19p dampens the p19ARF-p53-p21WAF1 tumor suppressor pathway. J Biol Chem. 2001 Jun 1;276(22):18649-52. Epub 2001 Mar 19. PMID:11259404 doi:10.1074/jbc.C100011200
↑ Mayerhofer PU, Kattenfeld T, Roscher AA, Muntau AC. Two splice variants of human PEX19 exhibit distinct functions in peroxisomal assembly. Biochem Biophys Res Commun. 2002 Mar 15;291(5):1180-6. PMID:11883941 doi:10.1006/bbrc.2002.6568
↑ Fang Y, Morrell JC, Jones JM, Gould SJ. PEX3 functions as a PEX19 docking factor in the import of class I peroxisomal membrane proteins. J Cell Biol. 2004 Mar 15;164(6):863-75. Epub 2004 Mar 8. PMID:15007061 doi:10.1083/jcb.200311131
↑ Jones JM, Morrell JC, Gould SJ. PEX19 is a predominantly cytosolic chaperone and import receptor for class 1 peroxisomal membrane proteins. J Cell Biol. 2004 Jan 5;164(1):57-67. PMID:14709540 doi:10.1083/jcb.200304111
↑ Emmanouilidis L, Schutz U, Tripsianes K, Madl T, Radke J, Rucktaschel R, Wilmanns M, Schliebs W, Erdmann R, Sattler M. Allosteric modulation of peroxisomal membrane protein recognition by farnesylation of the peroxisomal import receptor PEX19. Nat Commun. 2017 Mar 10;8:14635. doi: 10.1038/ncomms14635. PMID:28281558 doi:http://dx.doi.org/10.1038/ncomms14635

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5lnf"

@@ Line 1: / Line 1: @@
 ==Solution NMR structure of farnesylated PEX19, C-terminal domain==
-<StructureSection load='5lnf' size='340' side='right' caption='[[5lnf]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''>
+<StructureSection load='5lnf' size='340' side='right'caption='[[5lnf]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5lnf]] is a 1 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5LNF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5LNF FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5lnf]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5LNF OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5LNF FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FAR:FARNESYL'>FAR</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FAR:FARNESYL'>FAR</scene></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5lnf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5lnf OCA], [http://pdbe.org/5lnf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5lnf RCSB], [http://www.ebi.ac.uk/pdbsum/5lnf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5lnf ProSAT]</span></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PEX19, HK33, PXF, OK/SW-cl.22 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5lnf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5lnf OCA], [http://pdbe.org/5lnf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5lnf RCSB], [http://www.ebi.ac.uk/pdbsum/5lnf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5lnf ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 24: / Line 25: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Emmanouilidis, L]]
 [[Category: Erdmann, R]]

5lnf

From Proteopedia

Revision as of 10:43, 12 August 2020

Solution NMR structure of farnesylated PEX19, C-terminal domain

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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