Ubiquitin ligases of the N-END rule pathway

Assessment of mutations in UBR1 that cause the Johanson-Blizzard syndrome

Cheol Sang Hwang, Maja Sukalo, Olga Batygin, Marie Claude Addor, Han Brunner, Antonio Perez Aytes, Julia Mayerle, Hyun Kyu Song, Alexander Varshavsky, Martin Zenker

Research output: Contribution to journalArticle

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Abstract

Background: Johanson-Blizzard syndrome (JBS; OMIM 243800) is an autosomal recessive disorder that includes congenital exocrine pancreatic insufficiency, facial dysmorphism with the characteristic nasal wing hypoplasia, multiple malformations, and frequent mental retardation. Our previous work has shown that JBS is caused by mutations in human UBR1, which encodes one of the E3 ubiquitin ligases of the N-end rule pathway. The N-end rule relates the regulation of the in vivo half-life of a protein to the identity of its N-terminal residue. One class of degradation signals (degrons) recognized by UBR1 are destabilizing N-terminal residues of protein substrates. Methodology/Principal Findings: Most JBS-causing alterations of UBR1 are nonsense, frameshift or splice-site mutations that abolish UBR1 activity. We report here missense mutations of human UBR1 in patients with milder variants of JBS. These single-residue changes, including a previously reported missense mutation, involve positions in the RING-H2 and UBR domains of UBR1 that are conserved among eukaryotes. Taking advantage of this conservation, we constructed alleles of the yeast Saccharomyces cerevisiae UBR1 that were counterparts of missense JBS-UBR1 alleles. Among these yeast Ubr1 mutants, one of them (H160R) was inactive in yeast-based activity assays, the other one (Q1224E) had a detectable but weak activity, and the third one (V146L) exhibited a decreased but significant activity, in agreement with manifestations of JBS in the corresponding JBS patients. Conclusions/Significance: These results, made possible by modeling defects of a human ubiquitin ligase in its yeast counterpart, verified and confirmed the relevance of specific missense UBR1 alleles to JBS, and suggested that a residual activity of a missense allele is causally associated with milder variants of JBS.

Original languageEnglish
Article numbere24925
JournalPLoS One
Volume6
Issue number9
DOIs
Publication statusPublished - 2011 Sep 13

Fingerprint

Ligases
ubiquitin
Ubiquitin
ligases
Yeast
Yeasts
Alleles
yeasts
alleles
mutation
Mutation
missense mutation
Missense Mutation
Genetic Databases
Exocrine Pancreatic Insufficiency
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
ubiquitin-protein ligase
Ubiquitin-Protein Ligases
Eukaryota
Nose

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Hwang, C. S., Sukalo, M., Batygin, O., Addor, M. C., Brunner, H., Aytes, A. P., ... Zenker, M. (2011). Ubiquitin ligases of the N-END rule pathway: Assessment of mutations in UBR1 that cause the Johanson-Blizzard syndrome. PLoS One, 6(9), [e24925]. https://doi.org/10.1371/journal.pone.0024925

Ubiquitin ligases of the N-END rule pathway : Assessment of mutations in UBR1 that cause the Johanson-Blizzard syndrome. / Hwang, Cheol Sang; Sukalo, Maja; Batygin, Olga; Addor, Marie Claude; Brunner, Han; Aytes, Antonio Perez; Mayerle, Julia; Song, Hyun Kyu; Varshavsky, Alexander; Zenker, Martin.

In: PLoS One, Vol. 6, No. 9, e24925, 13.09.2011.

Research output: Contribution to journalArticle

Hwang, CS, Sukalo, M, Batygin, O, Addor, MC, Brunner, H, Aytes, AP, Mayerle, J, Song, HK, Varshavsky, A & Zenker, M 2011, 'Ubiquitin ligases of the N-END rule pathway: Assessment of mutations in UBR1 that cause the Johanson-Blizzard syndrome', PLoS One, vol. 6, no. 9, e24925. https://doi.org/10.1371/journal.pone.0024925
Hwang, Cheol Sang ; Sukalo, Maja ; Batygin, Olga ; Addor, Marie Claude ; Brunner, Han ; Aytes, Antonio Perez ; Mayerle, Julia ; Song, Hyun Kyu ; Varshavsky, Alexander ; Zenker, Martin. / Ubiquitin ligases of the N-END rule pathway : Assessment of mutations in UBR1 that cause the Johanson-Blizzard syndrome. In: PLoS One. 2011 ; Vol. 6, No. 9.
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AU - Aytes, Antonio Perez

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