Programmed trade-offs in protein folding networks

Maintaining protein homeostasis, i.e. a folded and functional proteome, depends on the efficient allocation of cellular protein quality control resources. Decline and dysregulation of protein homeostasis are directly associated to conditions of aging and neurodegeneration. Molecular chaperones as specialized protein quality control enzymes form the core of protein homeostasis. However, 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 the Saccharomyces cerevisiae Hsp70 Ssb. Structural homologues 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. All analyzed characteristics contributed to the prediction of Ssb interactions in highly complementary manner, highlighting pervasive trade-offs in chaperone-assisted protein folding landscapes. However, short discriminative sequences were found to contribute by far the strongest signal towards 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.