Many chaperones favour binding to hydrophobic sequences that are flanked by basic residues while disfavouring acidic residues. However, the origin of this bias in protein quality control remains poorly understood. Here, we show that while acidic residues are the most efficient aggregation inhibitors, they are also less compatible with globular protein structure than basic amino acids. As a result, while acidic residues allow for chaperone‐independent control of aggregation, their use is structurally limited. Conversely, we find that, while being more compatible with globular structure, basic residues are not sufficient to autonomously suppress protein aggregation. Using Hsp70, we show that chaperones with a bias towards basic residues are structurally adapted to prioritize aggregating sequences whose structural context forced the use of the less effective basic residues. The hypothesis that emerges from our analysis is that the bias of many chaperones for basic residues results from fundamental thermodynamic and kinetic constraints of globular structure. This also suggests the co‐evolution of basic residues and chaperones allowed for an expansion of structural variety in the protein universe.

Otosclerosis is one of the most common causes of hearing loss in young adults. It has a prevalence of 0.3–0.4% in the European population. Clinical symptoms usually occur between the second and fifth decade of life. Different studies have been performed to unravel the genetic architecture of the disease. Recently, a genome-wide association study (GWAS) identified 15 novel risk loci and replicated the regions of three previously reported candidate genes. In this study, seven candidate genes from the GWAS were resequenced using single molecule molecular inversion probes (smMIPs). smMIPs were used to capture the exonic regions and the 3′ and 5′ untranslated regions (UTR). Discovered variants were tested for association with the disease using single variant and gene-based association analysis. The single variant results showed that 13 significant variants were associated with otosclerosis. Associated variants were found in five of the seven genes studied here, including AHSG, LINC01482, MARK3, SUPT3H and RELN. Conversely, burden testing did not show a major role of rare variants in the disease. In conclusion, this study was able to replicate five out of seven candidate genes reported in the previous GWAS. This association is likely mainly driven by common variants.