Structure-function relationships of the soluble form of the antiaging protein Klotho have therapeutic implications for managing kidney disease
Xiaotian Zhong, Srinath Jagarlapudi, Yan Weng, Mellisa Ly, Jason C. Rouse, Kim F. McClure, Tetsuya Ishino, Yan Zhang, Eric Sousa, Justin Cohen, Boriana Tzvetkova, Kaffa Cote, John J. Scarcelli, Keith E. Johnson, Joe Palandra, James R. Apgar, Suma Yaddanapudi, Romer A. González-Villalobos, Alan Opsahl, Khetemenee Lam, Qing Yao, Weili Duan, Annette Sievers, Jing Zhou, Darren E. Ferguson, Aaron M. D’Antona, Richard Zollner, Hongli Zhu, Ron Kriz, Laura Lin, Valérie Clerin
Abstract
-glycans in Klotho's protein folding and function. Moreover, the introduction of two catalytic glutamate residues conserved across glycosidases into sKlotho enhanced its glucuronidase activity but decreased its FGF23 co-receptor activity, suggesting that these two functions might be structurally divergent. These findings open up opportunities for rational engineering of pharmacologically enhanced sKlotho therapeutics for managing kidney disease.