| Structural highlights
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]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The protein Pex19p functions as a receptor and chaperone of peroxisomal membrane proteins (PMPs). The crystal structure of the folded C-terminal part of the receptor reveals a globular domain that displays a bundle of three long helices in an antiparallel arrangement. Complementary functional experiments, using a range of truncated Pex19p constructs, show that the structured alpha-helical domain binds PMP-targeting signal (mPTS) sequences with about 10 muM affinity. Removal of a conserved N-terminal helical segment from the mPTS recognition domain impairs the ability for mPTS binding, indicating that it forms part of the mPTS-binding site. Pex19p variants with mutations in the same sequence segment abolish correct cargo import. Our data indicate a divided N-terminal and C-terminal structural arrangement in Pex19p, which is reminiscent of a similar division in the Pex5p receptor, to allow separation of cargo-targeting signal recognition and additional functions.
The peroxisomal receptor Pex19p forms a helical mPTS recognition domain.,Schueller N, Holton SJ, Fodor K, Milewski M, Konarev P, Stanley WA, Wolf J, Erdmann R, Schliebs W, Song YH, Wilmanns M EMBO J. 2010 Aug 4;29(15):2491-500. Epub 2010 Jun 8. PMID:20531392[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
- ↑ Schueller N, Holton SJ, Fodor K, Milewski M, Konarev P, Stanley WA, Wolf J, Erdmann R, Schliebs W, Song YH, Wilmanns M. The peroxisomal receptor Pex19p forms a helical mPTS recognition domain. EMBO J. 2010 Aug 4;29(15):2491-500. Epub 2010 Jun 8. PMID:20531392 doi:10.1038/emboj.2010.115
|
