Molecular chaperones as specialized protein quality control enzymes form the core of cellular protein homeostasis. How chaperones selectively interact with their substrate proteins thus allocate their overall limited capacity remains poorly understood. Here, I present an integrated analysis of sequence and structural determinants that define interactions of protein domains as the basic protein folding unit with the Saccharomyces cerevisiae Hsp70 Ssb. Structural homologs of single-domain proteins that differentially interact with Ssb for de novo folding were found to systematically differ in complexity of their folding landscapes, selective use of nonoptimal codons, and presence of short discriminative sequences, thus highlighting pervasive trade-offs in chaperone-assisted protein folding landscapes. However, short discriminative sequences were found to contribute by far the strongest signal toward explaining Ssb interactions. This observation suggested that some chaperone interactions may be directly programmed in the amino acid sequences rather than responding to folding challenges, possibly for regulatory advantages.
Keywords: Hsp70; chaperone specificity; homology modeling; protein family; protein folding; structural systems biology.
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