Date of Award
Yong Y.Y. Yu
Matteo M.R. Ruggiu
Yan Y.Z. Zhu
Autosomal dominant polycystic kidney disease (ADPKD), one of the most common and life-threatening human genetic diseases, is caused by mutations in PKD1 or PKD2 genes. PKD1 gene encodes PKD1 (also known as polycystin-1 or PC1) protein, which are the founding members of the PKD1 proteins family; while PKD2 encodes TRPP2 (also known as polycystin-2 or PC2) protein, the founding member of the TRPP subfamily. PKD1 family consists of PKD1, PKD1L1, PKD1L2, PKD1L3, and PKDREJ. Whereas the TRPP subfamily includes: TRPP2, TRPP3, and TRPP5. Proteins in PKD1 and TRPP families are collectively called polycystins. TRPP proteins can either form homotetrameric ion channels or assemble with proteins in the PKD1 family to form heterotetrameric ion channels. These ion channels are involved in various physiological processes ranging from development to vascular and neural activity, although the molecular mechanisms of their gating and function in vivo are largely unknown. My Ph.D. study was focused on the structure and function of two polycystin ion channels. In the first project, I worked on the PKD1L3/TRPP3 complex channel, which is involved in sour taste. Being currently the only polycystin channel that can be easily gated in experiments, the PKD1L3/TRPP3 complex is an ideal model for studying the gating mechanism of the polycystin proteins. In this study, we first identified a core fragment that retains the full function of the channel. With the help of the cryo-EM structure resolved by our collaborators, we were able to elucidate the possible molecular and structural basis of the Ca2+-induced activation of this channel. Our results significantly enhanced the understanding of the structure and functional regulation of the heteromeric polycystin channels. In the second project, I focused on the homomeric TRPP2 channel. How mutations in TRPP2 lead to ADPKD is elusive. In this study, we systematically tested the effects of 31-point mutations on the ion channel activity of a gain-of-function TRPP2 mutant, TRPP2_F604P, and discussed possible conformational consequences of these mutations based on reported cryo-EM structures. The results help gain insight into the structure and function of the TRPP2 ion channel and the molecular mechanism of pathogenesis caused by these mutations.
Wang, Yan, "GATING AND PATHOGENIC MECHANISM OF POLYCYSTIN ION CHANNELS" (2023). Theses and Dissertations. 599.