| Structural highlights
Disease
[SPYA_HUMAN] Defects in AGXT are the cause of hyperoxaluria primary type 1 (HP1) [MIM:259900]; also known as primary hyperoxaluria type I (PH1) and oxalosis I. HP1 is a rare autosomal recessive inborn error of glyoxylate metabolism characterized by increased excretion of oxalate and glycolate, and the progressive accumulation of insoluble calcium oxalate in the kidney and urinary tract.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [PEX5_HUMAN] Defects in PEX5 are the cause of peroxisome biogenesis disorder 2A (PBD2A) [MIM:214110]. A fatal peroxisome biogenesis disorder belonging to the Zellweger disease spectrum and characterized clinically 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.[19] Defects in PEX5 are the cause of peroxisome biogenesis disorder 2B (PBD2B) [MIM:202370]. A peroxisome biogenesis disorder that includes neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD), two milder manifestations of the Zellweger disease spectrum. The clinical course of patients with the NALD and IRD presentation is variable and may include developmental delay, hypotonia, liver dysfunction, sensorineural hearing loss, retinal dystrophy and vision impairment. Children with the NALD presentation may reach their teens, while patients with the IRD presentation may reach adulthood. The clinical conditions are often slowly progressive in particular with respect to loss of hearing and vision. The biochemical abnormalities include accumulation of phytanic acid, very long chain fatty acids (VLCFA), di- and trihydroxycholestanoic acid and pipecolic acid.
Function
[PEX5_HUMAN] Binds to the C-terminal PTS1-type tripeptide peroxisomal targeting signal (SKL-type) and plays an essential role in peroxisomal protein import.[20] [21] [22]
Publication Abstract from PubMed
Peroxisomes entirely rely on the import of their proteome across the peroxisomal membrane. Recognition efficiencies of peroxisomal proteins vary by more than 1000-fold but the molecular rationale behind their subsequent differential import and sorting has remained enigmatic. Using the protein cargo alanine-glyoxylate aminotransferase as a model, we have discovered an unexpected increase from 34% to 80% in peroxisomal import efficiency of a single-residue mutant. By high-resolution structural analysis, we found that it is the recognition receptor PEX5 that adapts its conformation for high-affinity binding rather than the cargo protein signal motif as previously thought. During receptor recognition, the binding cavity of the receptor shrinks to one third of its original volume. This process is impeded in the wild-type protein cargo because of a bulky side chain within the recognition motif, which blocks contraction of the PEX5 binding cavity. Our data provide a new insight on direct protein import efficiency by removal rather than addition of an apparent specific sequence signature that is generally applicable to peroxisomal matrix proteins and to other receptor recognition processes.
Ligand-induced compaction of the PEX5 receptor-binding cavity impacts protein import efficiency into peroxisomes.,Fodor K, Wolf J, Reglinski K, Passon DM, Lou Y, Schliebs W, Erdmann R, Wilmanns M Traffic. 2014 Nov 5. doi: 10.1111/tra.12238. PMID:25369882[23]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Purdue PE, Takada Y, Danpure CJ. Identification of mutations associated with peroxisome-to-mitochondrion mistargeting of alanine/glyoxylate aminotransferase in primary hyperoxaluria type 1. J Cell Biol. 1990 Dec;111(6 Pt 1):2341-51. PMID:1703535
- ↑ Nishiyama K, Funai T, Katafuchi R, Hattori F, Onoyama K, Ichiyama A. Primary hyperoxaluria type I due to a point mutation of T to C in the coding region of the serine:pyruvate aminotransferase gene. Biochem Biophys Res Commun. 1991 May 15;176(3):1093-9. PMID:2039493
- ↑ Purdue PE, Lumb MJ, Allsop J, Minatogawa Y, Danpure CJ. A glycine-to-glutamate substitution abolishes alanine:glyoxylate aminotransferase catalytic activity in a subset of patients with primary hyperoxaluria type 1. Genomics. 1992 May;13(1):215-8. PMID:1349575
- ↑ Minatogawa Y, Tone S, Allsop J, Purdue PE, Takada Y, Danpur CJ, Kido R. A serine-to-phenylalanine substitution leads to loss of alanine:glyoxylate aminotransferase catalytic activity and immunoreactivity in a patient with primary hyperoxaluria type 1. Hum Mol Genet. 1992 Nov;1(8):643-4. PMID:1301173
- ↑ Danpure CJ, Purdue PE, Fryer P, Griffiths S, Allsop J, Lumb MJ, Guttridge KM, Jennings PR, Scheinman JI, Mauer SM, et al.. Enzymological and mutational analysis of a complex primary hyperoxaluria type 1 phenotype involving alanine:glyoxylate aminotransferase peroxisome-to-mitochondrion mistargeting and intraperoxisomal aggregation. Am J Hum Genet. 1993 Aug;53(2):417-32. PMID:8101040
- ↑ von Schnakenburg C, Rumsby G. Primary hyperoxaluria type 1: a cluster of new mutations in exon 7 of the AGXT gene. J Med Genet. 1997 Jun;34(6):489-92. PMID:9192270
- ↑ von Schnakenburg C, Rumsby G. Identification of new mutations in primary hyperoxaluria type 1 (PH1). J Nephrol. 1998 Mar-Apr;11 Suppl 1:15-7. PMID:9604803
- ↑ Amoroso A, Pirulli D, Puzzer D, Ferri L, Crovella S, Ferrettini C, Marangella M, Mazzola G, Florian F. Gene symbol: AGXT. Disease: primary hyperoxaluria type I. Hum Genet. 1999 May;104(5):441. PMID:10394939
- ↑ Pirulli D, Puzzer D, Ferri L, Crovella S, Amoroso A, Ferrettini C, Marangella M, Mazzola G, Florian F. Molecular analysis of hyperoxaluria type 1 in Italian patients reveals eight new mutations in the alanine: glyoxylate aminotransferase gene. Hum Genet. 1999 Jun;104(6):523-5. PMID:10453743
- ↑ Rinat C, Wanders RJ, Drukker A, Halle D, Frishberg Y. Primary hyperoxaluria type I: a model for multiple mutations in a monogenic disease within a distinct ethnic group. J Am Soc Nephrol. 1999 Nov;10(11):2352-8. PMID:10541294
- ↑ Basmaison O, Rolland MO, Cochat P, Bozon D. Identification of 5 novel mutations in the AGXT gene. Hum Mutat. 2000 Jun;15(6):577. PMID:10862087 doi:<577::AID-HUMU9>3.0.CO;2-# 10.1002/1098-1004(200006)15:6<577::AID-HUMU9>3.0.CO;2-#
- ↑ Lumb MJ, Danpure CJ. Functional synergism between the most common polymorphism in human alanine:glyoxylate aminotransferase and four of the most common disease-causing mutations. J Biol Chem. 2000 Nov 17;275(46):36415-22. PMID:10960483 doi:10.1074/jbc.M006693200
- ↑ Coulter-Mackie MB, Tung A, Henderson HE, Toone JR, Applegarth DA. The AGT gene in Africa: a distinctive minor allele haplotype, a polymorphism (V326I), and a novel PH1 mutation (A112D) in Black Africans. Mol Genet Metab. 2003 Jan;78(1):44-50. PMID:12559847
- ↑ Santana A, Salido E, Torres A, Shapiro LJ. Primary hyperoxaluria type 1 in the Canary Islands: a conformational disease due to I244T mutation in the P11L-containing alanine:glyoxylate aminotransferase. Proc Natl Acad Sci U S A. 2003 Jun 10;100(12):7277-82. Epub 2003 May 30. PMID:12777626 doi:10.1073/pnas.1131968100
- ↑ van Woerden CS, Groothoff JW, Wijburg FA, Annink C, Wanders RJ, Waterham HR. Clinical implications of mutation analysis in primary hyperoxaluria type 1. Kidney Int. 2004 Aug;66(2):746-52. PMID:15253729 doi:10.1111/j.1523-1755.2004.00796.x
- ↑ Monico CG, Olson JB, Milliner DS. Implications of genotype and enzyme phenotype in pyridoxine response of patients with type I primary hyperoxaluria. Am J Nephrol. 2005 Mar-Apr;25(2):183-8. Epub 2005 Apr 21. PMID:15849466 doi:10.1159/000085411
- ↑ Frishberg Y, Rinat C, Shalata A, Khatib I, Feinstein S, Becker-Cohen R, Weismann I, Wanders RJ, Rumsby G, Roels F, Mandel H. Intra-familial clinical heterogeneity: absence of genotype-phenotype correlation in primary hyperoxaluria type 1 in Israel. Am J Nephrol. 2005 May-Jun;25(3):269-75. Epub 2005 Jun 15. PMID:15961946 doi:10.1159/000086357
- ↑ Coulter-Mackie MB, Lian Q, Applegarth D, Toone J. The major allele of the alanine:glyoxylate aminotransferase gene: nine novel mutations and polymorphisms associated with primary hyperoxaluria type 1. Mol Genet Metab. 2005 Sep-Oct;86(1-2):172-8. Epub 2005 Jun 15. PMID:15963748 doi:10.1016/j.ymgme.2005.05.005
- ↑ Dodt G, Braverman N, Wong C, Moser A, Moser HW, Watkins P, Valle D, Gould SJ. Mutations in the PTS1 receptor gene, PXR1, define complementation group 2 of the peroxisome biogenesis disorders. Nat Genet. 1995 Feb;9(2):115-25. PMID:7719337 doi:http://dx.doi.org/10.1038/ng0295-115
- ↑ Dodt G, Braverman N, Wong C, Moser A, Moser HW, Watkins P, Valle D, Gould SJ. Mutations in the PTS1 receptor gene, PXR1, define complementation group 2 of the peroxisome biogenesis disorders. Nat Genet. 1995 Feb;9(2):115-25. PMID:7719337 doi:http://dx.doi.org/10.1038/ng0295-115
- ↑ Wiemer EA, Nuttley WM, Bertolaet BL, Li X, Francke U, Wheelock MJ, Anne UK, Johnson KR, Subramani S. Human peroxisomal targeting signal-1 receptor restores peroxisomal protein import in cells from patients with fatal peroxisomal disorders. J Cell Biol. 1995 Jul;130(1):51-65. PMID:7790377
- ↑ Fransen M, Brees C, Baumgart E, Vanhooren JC, Baes M, Mannaerts GP, Van Veldhoven PP. Identification and characterization of the putative human peroxisomal C-terminal targeting signal import receptor. J Biol Chem. 1995 Mar 31;270(13):7731-6. PMID:7706321
- ↑ Fodor K, Wolf J, Reglinski K, Passon DM, Lou Y, Schliebs W, Erdmann R, Wilmanns M. Ligand-induced compaction of the PEX5 receptor-binding cavity impacts protein import efficiency into peroxisomes. Traffic. 2014 Nov 5. doi: 10.1111/tra.12238. PMID:25369882 doi:http://dx.doi.org/10.1111/tra.12238
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