The nanomechanics of polycystin-1: A kidney mechanosensor

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Mutations in polycystin-1 (PC1) can cause Autosomal Dominant Polycystic Kidney Disease (ADPKD), which is a leading cause of renal failure. The available evidence suggests that PC1 acts as a mechanosensor, receiving signals from the primary cilia, neighboring cells, and extracellular matrix. PC1 is a large membrane protein that has a long N-terminal extracellular region (about 3000 aa) with a multimodular structure including sixteen Ig-like PKD domains, which are targeted by many naturally occurring missense mutations. Nothing is known about the effects of these mutations on the biophysical properties of PKD domains. In addition, PC1 is expressed along the renal tubule, where it is exposed to a wide range of concentration of urea. Urea is known to destabilize proteins. Other osmolytes found in the kidney such as sorbitol, betaine and TMAO are known to counteract urea¡¯s negative effects on proteins. Nothing is known about how the mechanical properties of PC1 are affected by these osmolytes. Here I use nano-mechanical techniques to study the effects of missense mutations and effects of denaturants and various osmolytes on the mechanical properties of PKD domains. Several missense mutations were found to alter the mechanical stability of PKD domains resulting in distinct mechanical phenotypes. Based on these findings, I hypothesize that missense mutations may cause ADPKD by altering the stability of the PC1 ectodomain, thereby perturbing its ability to sense mechanical signals. I also found that urea has a significant impact on both the mechanical stability and refolding rate of PKD domains. It not only lowers their mechanical stability, but also slows down their refolding rate. Moreover, several osmolytes were found to effectively counteract the effects of urea. Our data provide the evidence that naturally occurring osmolytes can help to maintain Polycystin-1 mechanical stability and folding kinetics. This study has the potential to provide new therapeutic approaches (e.g. through the use of osmolytes or chemical chaperones) for rescuing destabilized and misfolded PKD domains.

polycystin-1, osmolyte, Missense mutations, mechanosensor, atomic force microscopy, ADPKD