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-Structure paper
Title | Structural basis of TRPV5 regulation by physiological and pathophysiological modulators. |
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Journal, issue, pages | Cell Rep, Vol. 39, Issue 4, Page 110737, Year 2022 |
Publish date | Apr 26, 2022 |
Authors | Edwin C Fluck / Aysenur Torun Yazici / Tibor Rohacs / Vera Y Moiseenkova-Bell / |
PubMed Abstract | Transient receptor potential vanilloid 5 (TRPV5) is a kidney-specific Ca-selective ion channel that plays a key role in Ca homeostasis. The basal activity of TRPV5 is balanced through activation by ...Transient receptor potential vanilloid 5 (TRPV5) is a kidney-specific Ca-selective ion channel that plays a key role in Ca homeostasis. The basal activity of TRPV5 is balanced through activation by phosphatidylinositol 4,5-bisphosphate (PI(4,5)P) and inhibition by Ca-bound calmodulin (CaM). Parathyroid hormone (PTH), the key extrinsic regulator of Ca homeostasis, increases the activity of TRPV5 via protein kinase A (PKA)-mediated phosphorylation. Metabolic acidosis leads to reduced TRPV5 activity independent of PTH, causing hypercalciuria. Using cryoelectron microscopy (cryo-EM), we show that low pH inhibits TRPV5 by precluding PI(4,5)P activation. We capture intermediate conformations at low pH, revealing a transition from open to closed state. In addition, we demonstrate that PI(4,5)P is the primary modulator of channel gating, yet PKA controls TRPV5 activity by preventing CaM binding and channel inactivation. Our data provide detailed molecular mechanisms for regulation of TRPV5 by two key extrinsic modulators, low pH and PKA. |
External links | Cell Rep / PubMed:35476976 / PubMed Central |
Methods | EM (single particle) |
Resolution | 2.6 - 4.2 Å |
Structure data | EMDB-25716, PDB-7t6j: EMDB-25717, PDB-7t6k: EMDB-25718, PDB-7t6l: EMDB-25719, PDB-7t6m: EMDB-25720, PDB-7t6n: EMDB-25721, PDB-7t6o: EMDB-25722: Cryo-EM structure of TRPV5 in detergent in the presence of PKA EMDB-25723, PDB-7t6p: EMDB-25724, PDB-7t6q: EMDB-25725, PDB-7t6r: |
Chemicals | ChemComp-PIO: |
Source |
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Keywords | TRANSPORT PROTEIN / Calcium / Ion channel / Kidney |