Title: Selectivity of aggregation-determining interactions
Authors: Ganesan, Ashok
Debulpaep, Maja
Wilkinson, Hannah
Van Durme, Joost
De Baets, Greet
Jonckheere, Wim
Ramakers, Meine
Ivarsson, Ylva
Zimmermann, Pascale
Van Eldere, Johan
Schymkowitz, Joost #
Rousseau, Frederic # ×
Issue Date: Jan-2015
Publisher: Academic Press
Series Title: Journal of Molecular Biology vol:427 issue:2 pages:236-47
Article number: 10.1016/j.jmb.2014.09.027
Abstract: Protein aggregation is sequence specific, favoring self-assembly over cross-seeding with non-homologous sequences. Still, as the majority of proteins in a proteome are aggregation prone, the high level of homogeneity of protein inclusions in vivo both during recombinant overexpression and in disease remains surprising. To investigate the selectivity of protein aggregation in a proteomic context, we here compared the selectivity of aggregation-determined interactions with antibody binding. To that purpose, we synthesized biotin-labeled peptides, corresponding to aggregation-determining sequences of the bacterial protein β-galactosidase and two human disease biomarkers: C-reactive protein and prostate-specific antigen. We analyzed the selectivity of their interactions in Escherichia coli lysate, human serum and human seminal plasma, respectively, using a Western blot-like approach in which the aggregating peptides replace the conventional antibody. We observed specific peptide accumulation in the same bands detected by antibody staining. Combined spectroscopic and mutagenic studies confirmed accumulation resulted from binding of the peptide on the identical sequence of the immobilized target protein. Further, we analyzed the sequence redundancy of aggregating sequences and found that about 90% of them are unique within their proteome. As a result, the combined specificity and low sequence redundancy of aggregating sequences therefore contribute to the observed homogeneity of protein aggregation in vivo. This suggests that these intrinsic proteomic properties naturally compartmentalize aggregation events in sequence space. In the event of physiological stress, this might benefit the ability of cells to respond to proteostatic stress by allowing chaperones to focus on specific aggregation events rather than having to face systemic proteostatic failure.
ISSN: 0022-2836
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Switch Laboratory
Department of Human Genetics - miscellaneous
Laboratory of Clinical Bacteriology and Mycology
× corresponding author
# (joint) last author

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