Abstract
Molecular chaperones ensure that their substrate proteins reach the functional native state and prevent their aggregation. The bacterial GroEL/ES chaperonin system is understood in great detail on a structural, mechanistic and functional level. Its substrate proteins in E. coli have been identified and characterized. However, a long standing and yet unresolved question in the field is: what makes a protein a chaperone substrate?Here we demonstrate with a bioinformatics-based approach that a simple set of criteria is sufficient to describe the GroEL substrate proteome to unprecedented accuracy. We define two novel parameters differentiating GroEL substrates from other cellular proteins: evolutionary rate and hydrophobicity. We demonstrate their conjunct applicability and explain why they are suitable descriptors. Combining them with other specific features of proteins, such as structure and size, we manage to identify the subset of GroEL substrate proteins with high confidence. We verify the applicability of our findings by correctly predicting a number of known heterologous GroEL substrate proteins.Furthermore, our results show that in vivo, the proposed buffering capacity of chaperones does not appear to be a dominant effect. Instead, the observed lower evolutionary rates among substrate proteins could be explained by their energetically unfavorable folding pathways not allowing for additional destabilizing mutations to occur.We show that a combination of simple parameters is sufficient to accurately describe the GroEL substrate proteome and to successfully predict known heterologous substrates. Our approach can potentially be used to predict chaperonin usage for any given polypeptide chain. Observed low evolutionary rates of GroEL substrates suggest that constraints in the folding pathways of the respective proteins do not allow for the accumulation of mutations.
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Raineri, E., Ribeca, P., Serrano, L. et al. Novel determinants describe chaperonin substrate proteins. Nat Prec (2009). https://doi.org/10.1038/npre.2009.2968.2
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DOI: https://doi.org/10.1038/npre.2009.2968.2