7T6R

Cryo-EM structure of TRPV5 T709D in nanodiscs in the presence of Calmodulin

Summary for 7T6R

• Entry DOI: 10.2210/pdb7t6r/pdb
• EMDB information: 25716 25717 25718 25719 25720 25721 25722 25723 25724 25725
• Descriptor: Transient receptor potential cation channel subfamily V member 5 (1 entity in total)
• Functional Keywords: calcium, ion channel, kidney, transport protein
• Biological source: Oryctolagus cuniculus (rabbit)
• Total number of polymer chains: 4
• Total formula weight: 335194.28

Authors

Fluck, E.C.,Yazici, A.T.,Rohacs, T.,Moiseenkova-Bell, V.Y. (deposition date: 2021-12-14, release date: 2022-05-04, Last modification date: 2024-02-28)

Primary citation

Fluck, E.C.,Yazici, A.T.,Rohacs, T.,Moiseenkova-Bell, V.Y.
Structural basis of TRPV5 regulation by physiological and pathophysiological modulators.
Cell Rep, 39:110737-110737, 2022

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 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.

PubMed: 35476976
DOI: 10.1016/j.celrep.2022.110737

Experimental method

ELECTRON MICROSCOPY (3 Å)