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-Structure paper
タイトル | Structural basis of TRPV5 regulation by physiological and pathophysiological modulators. |
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ジャーナル・号・ページ | Cell Rep, Vol. 39, Issue 4, Page 110737, Year 2022 |
掲載日 | 2022年4月26日 |
著者 | Edwin C Fluck / Aysenur Torun Yazici / Tibor Rohacs / Vera Y Moiseenkova-Bell / |
PubMed 要旨 | 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. |
リンク | Cell Rep / PubMed:35476976 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 2.6 - 4.2 Å |
構造データ | 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: |
化合物 | ChemComp-PIO: |
由来 |
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キーワード | TRANSPORT PROTEIN / Calcium / Ion channel / Kidney |