11 April 2019

The transient receptor potential (TRP) channel superfamily is one of the largest classes of cation channels fulfilling an enormous diversity in physiological functions. In order to advance studies on the emerging number of TRP channel-related diseases and guide effective treatment, it is essential to have detailed molecular understanding of their structure and function. However, for the longest time, TRP channels resisted all attempts at detailed structural investigation.

In collaboration with the groups of Yifan Cheng and David Julius (UCSF, San Francisco, USA), Mark van Goor and Jenny van der Wijst, theme Renal disorders, employed cryo-electron microscopy (cryo-EM) to resolve atomic-level details of TRPV5, which are now published in Proceedings of the National Academy of Sciences.

The 2017 Nobel Prize-awarded cryo-EM technology allows scientists to obtain thousands of snapshots of frozen protein molecules. Following, these individual pictures can be reconstructed into movie-like scenes that are used to build the complete image of a molecular machinery such as TRPV5. TRPV5 serves as a gatekeeper for calcium transport across epithelial cell membranes in the kidney, and thereby plays an important role in maintaining the body’s calcium balance. The 3D structure of TRPV5 is solved in complex with a protein called calmodulin, which is essential to channel regulation. They demonstrate that calmodulin directly plugs the pore of the channel and disclosed the structural mechanism of TRPV5 channel inactivation. The team of Jenny van der Wijst follows up this fundamental line of work to answer long-standing questions about TRPV5’s (patho)physiological role in calcium homeostasis. Genetic variants of the TRPV5 gene are associated with calcium loss in the urine, and predispose people to the formation of kidney stones. Their high-resolution insight may pave the way for future studies towards targeted therapies to modulate channel function in people suffering from kidney stones and related disorders.

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