3mk4

Structural highlights

Disease

[PEX3_HUMAN] Defects in PEX3 are the cause of peroxisome biogenesis disorder complementation group 12 (PBD-CG12) [MIM:614882]; also known as PBD-CGG. 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 PEX3 are a cause of peroxisome biogenesis disorder 10A (PBD10A) [MIM:614882]. A fatal peroxisome biogenesis disorder characterized by dysmorphic facial features, hepatomegaly, ocular abnormalities, renal cysts, hearing impairment, profound psychomotor retardation, severe hypotonia and neonatal seizures. Death occurs within the first year of life.^{[2] [3]} [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.^[4] 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

[PEX3_HUMAN] Involved in peroxisome biosynthesis and integrity. Assembles membrane vesicles before the matrix proteins are translocated. As a docking factor for PEX19, is necessary for the import of peroxisomal membrane proteins in the peroxisomes.^{[5] [6]} [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.^{[7] [8] [9] [10] [11] [12]}

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

References

1. ↑ Muntau AC, Mayerhofer PU, Paton BC, Kammerer S, Roscher AA. Defective peroxisome membrane synthesis due to mutations in human PEX3 causes Zellweger syndrome, complementation group G. Am J Hum Genet. 2000 Oct;67(4):967-75. Epub 2000 Aug 24. PMID:10958759 doi:S0002-9297(07)63288-1
2. ↑ Ghaedi K, Tamura S, Okumoto K, Matsuzono Y, Fujiki Y. The peroxin pex3p initiates membrane assembly in peroxisome biogenesis. Mol Biol Cell. 2000 Jun;11(6):2085-102. PMID:10848631
3. ↑ Muntau AC, Mayerhofer PU, Paton BC, Kammerer S, Roscher AA. Defective peroxisome membrane synthesis due to mutations in human PEX3 causes Zellweger syndrome, complementation group G. Am J Hum Genet. 2000 Oct;67(4):967-75. Epub 2000 Aug 24. PMID:10958759 doi:S0002-9297(07)63288-1
4. ↑ 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
5. ↑ Ghaedi K, Tamura S, Okumoto K, Matsuzono Y, Fujiki Y. The peroxin pex3p initiates membrane assembly in peroxisome biogenesis. Mol Biol Cell. 2000 Jun;11(6):2085-102. PMID:10848631
6. ↑ 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
7. ↑ 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
8. ↑ 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
9. ↑ 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
10. ↑ 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
11. ↑ 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
12. ↑ 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
13. ↑ Schmidt F, Treiber N, Zocher G, Bjelic S, Steinmetz MO, Kalbacher H, Stehle T, Dodt G. Insights into peroxisome function from the structure of PEX3 in complex with a soluble fragment of PEX19. J Biol Chem. 2010 Aug 13;285(33):25410-7. Epub 2010 Jun 16. PMID:20554521 doi:10.1074/jbc.M110.138503