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7ns7

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Human L-alanine:glyoxylate aminotransferase minor allele variant: AGXT-Mi (P11L-I340M)Human L-alanine:glyoxylate aminotransferase minor allele variant: AGXT-Mi (P11L-I340M)

Structural highlights

7ns7 is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
NonStd Res:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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]

Publication Abstract from PubMed

The conformational landscape of a protein is constantly expanded by genetic variations that have a minimal impact on the function(s) while causing subtle effects on protein structure. The wider the conformational space sampled by these variants, the higher the probabilities to adapt to changes in environmental conditions. However, the probability that a single mutation may result in a pathogenic phenotype also increases. Here we present a paradigmatic example of how protein evolution balances structural stability and dynamics to maximize protein adaptability and preserve protein fitness. We took advantage of known genetic variations of human alanine:glyoxylate aminotransferase (AGT1), which is present as a common major allelic form (AGT-Ma) and a minor polymorphic form (AGT-Mi) expressed in 20% of Caucasian population. By integrating crystallographic studies and molecular dynamics simulations, we show that AGT-Ma is endowed with structurally unstable (frustrated) regions, which become disordered in AGT-Mi. An in-depth biochemical characterization of variants from an anticonsensus library, encompassing the frustrated regions, correlates this plasticity to a fitness window defined by AGT-Ma and AGT-Mi. Finally, co-immunoprecipitation analysis suggests that structural frustration in AGT1 could favor additional functions related to protein-protein interactions. These results expand our understanding of protein structural evolution by establishing that naturally occurring genetic variations tip the balance between stability and frustration to maximize the ensemble of conformations falling within a well-defined fitness window, thus expanding the adaptability potential of the protein.

Structural dynamics shape the fitness window of alanine:glyoxylate aminotransferase.,Dindo M, Pascarelli S, Chiasserini D, Grottelli S, Costantini C, Uechi GI, Giardina G, Laurino P, Cellini B Protein Sci. 2022 May;31(5):e4303. doi: 10.1002/pro.4303. PMID:35481644[19]

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

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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
  5. ↑ 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
  6. ↑ 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
  7. ↑ 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
  8. ↑ 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
  9. ↑ 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
  10. ↑ 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
  11. ↑ 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-#
  12. ↑ 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
  13. ↑ 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
  14. ↑ 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
  15. ↑ 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
  16. ↑ 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
  17. ↑ 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
  18. ↑ 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
  19. ↑ Dindo M, Pascarelli S, Chiasserini D, Grottelli S, Costantini C, Uechi GI, Giardina G, Laurino P, Cellini B. Structural dynamics shape the fitness window of alanine:glyoxylate aminotransferase. Protein Sci. 2022 May;31(5):e4303. doi: 10.1002/pro.4303. PMID:35481644 doi:http://dx.doi.org/10.1002/pro.4303

7ns7, resolution 2.20Å

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