Natively entangled proteins are linked to human disease and pathogenic mutations likely due to a greater misfolding propensity.

A recently discovered class of protein misfolding involving native entanglements could be a widespread mechanism by which loss-of-function diseases arise. Here, we test that hypothesis by examining if there is any statistical association between proteins predisposed to misfold in this way and a database of gene-disease relationships. We find that globular proteins containing non-covalent lasso entanglements (NCLEs) in their native structure, which are more prone to misfolding, are 61% more likely to be associated with disease, 68% more likely to harbor pathogenic missense mutations, and their misfolding-prone entangled regions are 64% more likely to harbor pathogenic missense mutations. Protein refolding simulations indicate that these disease associated, natively entangled proteins are 2.5-times more likely to misfold than comparable non-disease proteins that lack native NCLEs. These results indicate that native entanglement misfolding, especially in the presence of missense mutations, have the potential to contribute to a wide variety of diseases. More broadly, these findings open an entirely new space of therapeutic targets in which drugs are designed to avoid these misfolded states and increase the amount of folded, functional protein.