1p4k Citations

A dual role for an aspartic acid in glycosylasparaginase autoproteolysis.

Structure 11 997-1003 (2003)
Cited: 19 times
EuropePMC logo PMID: 12906830

Abstract

Glycosylasparaginase uses an autoproteolytic processing mechanism, through an N-O acyl shift, to generate a mature/active enzyme from a single-chain precursor. Structures of glycosylasparaginase precursors in complex with a glycine inhibitor have revealed the backbone in the immediate vicinity of the scissile peptide bond to be in a distorted trans conformation, which is believed to be the driving force for the N-O acyl shift to break the peptide bond. Here we report the effects of point mutation D151N. In addition to the loss of the base essential in autoproteolysis, this mutation also eradicates the backbone distortion near the scissile peptide bond. Binding of the glycine inhibitor to the autoproteolytic site of the D151N mutant does not restore the backbone distortion. Therefore, Asp151 plays a dual role, acting as the general base to activate the nucleophile and holding the distorted trans conformation that is critical for initiating an N-O acyl shift.

Articles - 1p4k mentioned but not cited (3)

  1. Structural basis of a point mutation that causes the genetic disease aspartylglucosaminuria. Sui L, Lakshminarasimhan D, Pande S, Guo HC. Structure 22 1855-1861 (2014)
  2. Unraveling the Activation Mechanism of Taspase1 which Controls the Oncogenic AF4-MLL Fusion Protein. Sabiani S, Geppert T, Engelbrecht C, Kowarz E, Schneider G, Marschalek R. EBioMedicine 2 386-395 (2015)
  3. Crystal structure of a mutant glycosylasparaginase shedding light on aspartylglycosaminuria-causing mechanism as well as on hydrolysis of non-chitobiose substrate. Pande S, Lakshminarasimhan D, Guo HC. Mol. Genet. Metab. 121 150-156 (2017)


Articles citing this publication (16)

  1. MapQuant: open-source software for large-scale protein quantification. Leptos KC, Sarracino DA, Jaffe JD, Krastins B, Church GM. Proteomics 6 1770-1782 (2006)
  2. CARD8 and NLRP1 undergo autoproteolytic processing through a ZU5-like domain. D'Osualdo A, Weichenberger CX, Wagner RN, Godzik A, Wooley J, Reed JC. PLoS ONE 6 e27396 (2011)
  3. Crystal structure of isoaspartyl aminopeptidase in complex with L-aspartate. Michalska K, Brzezinski K, Jaskolski M. J Biol Chem 280 28484-28491 (2005)
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  8. Crystallographic snapshot of a productive glycosylasparaginase-substrate complex. Wang Y, Guo HC. J. Mol. Biol. 366 82-92 (2007)
  9. Free glycine accelerates the autoproteolytic activation of human asparaginase. Su Y, Karamitros CS, Nomme J, McSorley T, Konrad M, Lavie A. Chem. Biol. 20 533-540 (2013)
  10. Clostridium difficile cell wall protein CwpV undergoes enzyme-independent intramolecular autoproteolysis. Dembek M, Reynolds CB, Fairweather NF. J. Biol. Chem. 287 1538-1544 (2012)
  11. Elucidation of the specific function of the conserved threonine triad responsible for human L-asparaginase autocleavage and substrate hydrolysis. Nomme J, Su Y, Lavie A. J. Mol. Biol. 426 2471-2485 (2014)
  12. The N-terminal nucleophile serine of cephalosporin acylase executes the second autoproteolytic cleavage and acylpeptide hydrolysis. Yin J, Deng Z, Zhao G, Huang X. J. Biol. Chem. 286 24476-24486 (2011)
  13. Self-cleavage of the Pseudomonas aeruginosa Cell-surface Signaling Anti-sigma Factor FoxR Occurs through an N-O Acyl Rearrangement. Bastiaansen KC, van Ulsen P, Wijtmans M, Bitter W, Llamas MA. J. Biol. Chem. 290 12237-12246 (2015)
  14. Intramolecular Cleavage of the hASRGL1 Homodimer Occurs in Two Stages. Li W, Irani S, Crutchfield A, Hodge K, Matthews W, Patel P, Zhang YJ, Stone E. Biochemistry 55 960-969 (2016)
  15. Biochemical and structural insights into an allelic variant causing the lysosomal storage disorder - aspartylglucosaminuria. Pande S, Bizilj W, Guo HC. FEBS Lett. 592 2550-2561 (2018)
  16. The T99K variant of glycosylasparaginase shows a new structural mechanism of the genetic disease aspartylglucosaminuria. Pande S, Guo HC. Protein Sci 28 1013-1023 (2019)