Jie Xu

Publications (2)17.63 Total impact

• Article: Aggregation gatekeepers modulate protein homeostasis of aggregating sequences and affect bacterial fitness.

  Jacinte Beerten, Wim Jonckheere, Stanislav Rudyak, Jie Xu, Hannah Wilkinson, Frederik De Smet, Joost Schymkowitz, Frederic Rousseau
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  ABSTRACT: The most common mechanism by which proteins aggregate consists in the assembly of short hydrophobic primary sequence segments into extended β-structured agglomerates. A significant enrichment of charged residues is observed at the flank of these aggregation-prone sequence segments, suggesting selective pressure against aggregation. These so-called aggregation gatekeepers act by increasing the intrinsic solubility of aggregating sequences in vitro, but it has been suggested that they could also facilitate chaperone interactions. Here, we address whether aggregation gatekeepers affect bacterial fitness. In Escherichia coli MC4100 we overexpressed GFP fusions with an aggregation-prone segment of σ32 (further termed σ32β) flanked by gatekeeper and non-gatekeeper residues and measured pairwise competitive growth. We found that the identity of flanking residues had significant effect on bacterial growth. Overexpression of σ32β flanked by its natural gatekeepers displayed the greatest competitive fitness, followed by other combinations of gatekeepers, while absence of gatekeepers strongly affects bacterial fitness. Further analysis showed the diversity of effects of gatekeepers on the proteostasis of σ32β including synthesis and degradation rates, in vivo aggregation propensity and chaperone response. Our results suggest that gatekeeper residues affect bacterial fitness not only by modulating the intrinsic aggregation propensity of proteins but also by the manner in which they affect the processing of σ32β-GFP by the protein quality control machinery of the cell. In view of these observations, we hypothesize that variation at gatekeeper positions offers a flexible selective strategy to modulate the proteostatic regulation of proteins to the match intrinsic aggregation propensities of proteins with required expression levels.
  Protein Engineering Design and Selection 06/2012; 25(7):357-66. · 2.94 Impact Factor
• Article: Gain of function of mutant p53 by coaggregation with multiple tumor suppressors.

  Jie Xu, Joke Reumers, José R Couceiro, Frederik De Smet, Rodrigo Gallardo, Stanislav Rudyak, Ann Cornelis, Jef Rozenski, Aleksandra Zwolinska, Jean-Christophe Marine, Diether Lambrechts, Young-Ah Suh, Frederic Rousseau, Joost Schymkowitz
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  ABSTRACT: Many p53 missense mutations possess dominant-negative activity and oncogenic gain of function. We report that for structurally destabilized p53 mutants, these effects result from mutant-induced coaggregation of wild-type p53 and its paralogs p63 and p73, thereby also inducing a heat-shock response. Aggregation of mutant p53 resulted from self-assembly of a conserved aggregation-nucleating sequence within the hydrophobic core of the DNA-binding domain, which becomes exposed after mutation. Suppressing the aggregation propensity of this sequence by mutagenesis abrogated gain of function and restored activity of wild-type p53 and its paralogs. In the p53 germline mutation database, tumors carrying aggregation-prone p53 mutations have a significantly lower frequency of wild-type allele loss as compared to tumors harboring nonaggregating mutations, suggesting a difference in clonal selection of aggregating mutants. Overall, our study reveals a novel disease mechanism for mutant p53 gain of function and suggests that, at least in some respects, cancer could be considered an aggregation-associated disease.
  Nature Chemical Biology 03/2011; 7(5):285-95. · 14.69 Impact Factor