7t6o | pdb_00007t6o
Cryo-EM structure of TRPV5 in nanodiscs at pH6 state 3
Structural highlights
Function[TRPV5_RABIT] Constitutively active calcium selective cation channel thought to be involved in Ca(2+) reabsorption in kidney and intestine (PubMed:12574114). Required for normal Ca(2+) reabsorption in the kidney distal convoluted tubules (By similarity). The channel is activated by low internal calcium level and the current exhibits an inward rectification (By similarity). A Ca(2+)-dependent feedback regulation includes fast channel inactivation and slow current decay (By similarity). Heteromeric assembly with TRPV6 seems to modify channel properties. TRPV5-TRPV6 heteromultimeric concatemers exhibit voltage-dependent gating (PubMed:12574114).[UniProtKB:P69744][UniProtKB:Q9NQA5][1] [2] [3] Publication Abstract from PubMedTransient receptor potential vanilloid 5 (TRPV5) is a kidney-specific Ca(2+)-selective ion channel that plays a key role in Ca(2+) homeostasis. The basal activity of TRPV5 is balanced through activation by phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and inhibition by Ca(2+)-bound calmodulin (CaM). Parathyroid hormone (PTH), the key extrinsic regulator of Ca(2+) 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)P2 activation. We capture intermediate conformations at low pH, revealing a transition from open to closed state. In addition, we demonstrate that PI(4,5)P2 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. Structural basis of TRPV5 regulation by physiological and pathophysiological modulators.,Fluck EC, Yazici AT, Rohacs T, Moiseenkova-Bell VY Cell Rep. 2022 Apr 26;39(4):110737. doi: 10.1016/j.celrep.2022.110737. PMID:35476976[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||
