The nanomechanics of polycystin-1: A kidney mechanosensor

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Title: The nanomechanics of polycystin-1: A kidney mechanosensor
Author: Liang Ma
Abstract: 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 .
URI: http : / /hdl .handle .net /2152 .3 /143
Date: 2010-06-25

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The nanomechanics of polycystin-1: A kidney mechanosensor. Doctoral dissertation, The University of Texas Medical Branch. Available electronically from http : / /hdl .handle .net /2152 .3 /143 .

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