8jgs

From Proteopedia

(Difference between revisions)

Current revision

Cryo-EM structure of apo state mClC-3_I607T

Structural highlights

8jgs is a 2 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.96Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CLCN3_MOUSE May influence large dense-core vesicle exocytosis in adrenal chromaffin cells.^[1] Strongly outwardly rectifying, electrogenic H(+)/Cl(-)exchanger which mediates the exchange of chloride ions against protons (PubMed:26342074). The CLC channel family contains both chloride channels and proton-coupled anion transporters that exchange chloride or another anion for protons (By similarity). The presence of conserved gating glutamate residues is typical for family members that function as antiporters (By similarity).[UniProtKB:P51790]^[2] Strongly outwardly rectifying, electrogenic H(+)/Cl(-)exchanger which mediates the exchange of chloride ions against protons (PubMed:24603049, PubMed:26342074, PubMed:28972156). Facilitates endosomal acidification and chloride accumulation in hepatocytes (PubMed:15504734).^[3] ^[4] ^[5] ^[6] Strongly outwardly rectifying, electrogenic H(+)/Cl(-)exchanger which mediates the exchange of chloride ions against protons.^[7]

Publication Abstract from PubMed

The ClC-3 chloride/proton exchanger is both physiologically and pathologically critical, as it is potentiated by ATP to detect metabolic energy level and point mutations in ClC-3 lead to severe neurodegenerative diseases in human. However, why this exchanger is differentially modulated by ATP, ADP or AMP and how mutations caused gain-of-function remains largely unknow. Here we determine the high-resolution structures of dimeric wildtype ClC-3 in the apo state and in complex with ATP, ADP and AMP, and the disease-causing I607T mutant in the apo and ATP-bounded state by cryo-electron microscopy. In combination with patch-clamp recordings and molecular dynamic simulations, we reveal how the adenine nucleotides binds to ClC-3 and changes in ion occupancy between apo and ATP-bounded state. We further observe I607T mutation induced conformational changes and augments in current. Therefore, our study not only lays the structural basis of adenine nucleotides regulation in ClC-3, but also clearly indicates the target region for drug discovery against ClC-3 mediated neurodegenerative diseases.

Structural basis of adenine nucleotides regulation and neurodegenerative pathology in ClC-3 exchanger.,Wan Y, Guo S, Zhen W, Xu L, Chen X, Liu F, Shen Y, Liu S, Hu L, Wang X, Ye F, Wang Q, Wen H, Yang F Nat Commun. 2024 Aug 6;15(1):6654. doi: 10.1038/s41467-024-50975-w. PMID:39107281^[8]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Carninci P, Kasukawa T, Katayama S, Gough J, Frith MC, Maeda N, Oyama R, Ravasi T, Lenhard B, Wells C, Kodzius R, Shimokawa K, Bajic VB, Brenner SE, Batalov S, Forrest AR, Zavolan M, Davis MJ, Wilming LG, Aidinis V, Allen JE, Ambesi-Impiombato A, Apweiler R, Aturaliya RN, Bailey TL, Bansal M, Baxter L, Beisel KW, Bersano T, Bono H, Chalk AM, Chiu KP, Choudhary V, Christoffels A, Clutterbuck DR, Crowe ML, Dalla E, Dalrymple BP, de Bono B, Della Gatta G, di Bernardo D, Down T, Engstrom P, Fagiolini M, Faulkner G, Fletcher CF, Fukushima T, Furuno M, Futaki S, Gariboldi M, Georgii-Hemming P, Gingeras TR, Gojobori T, Green RE, Gustincich S, Harbers M, Hayashi Y, Hensch TK, Hirokawa N, Hill D, Huminiecki L, Iacono M, Ikeo K, Iwama A, Ishikawa T, Jakt M, Kanapin A, Katoh M, Kawasawa Y, Kelso J, Kitamura H, Kitano H, Kollias G, Krishnan SP, Kruger A, Kummerfeld SK, Kurochkin IV, Lareau LF, Lazarevic D, Lipovich L, Liu J, Liuni S, McWilliam S, Madan Babu M, Madera M, Marchionni L, Matsuda H, Matsuzawa S, Miki H, Mignone F, Miyake S, Morris K, Mottagui-Tabar S, Mulder N, Nakano N, Nakauchi H, Ng P, Nilsson R, Nishiguchi S, Nishikawa S, Nori F, Ohara O, Okazaki Y, Orlando V, Pang KC, Pavan WJ, Pavesi G, Pesole G, Petrovsky N, Piazza S, Reed J, Reid JF, Ring BZ, Ringwald M, Rost B, Ruan Y, Salzberg SL, Sandelin A, Schneider C, Schonbach C, Sekiguchi K, Semple CA, Seno S, Sessa L, Sheng Y, Shibata Y, Shimada H, Shimada K, Silva D, Sinclair B, Sperling S, Stupka E, Sugiura K, Sultana R, Takenaka Y, Taki K, Tammoja K, Tan SL, Tang S, Taylor MS, Tegner J, Teichmann SA, Ueda HR, van Nimwegen E, Verardo R, Wei CL, Yagi K, Yamanishi H, Zabarovsky E, Zhu S, Zimmer A, Hide W, Bult C, Grimmond SM, Teasdale RD, Liu ET, Brusic V, Quackenbush J, Wahlestedt C, Mattick JS, Hume DA, Kai C, Sasaki D, Tomaru Y, Fukuda S, Kanamori-Katayama M, Suzuki M, Aoki J, Arakawa T, Iida J, Imamura K, Itoh M, Kato T, Kawaji H, Kawagashira N, Kawashima T, Kojima M, Kondo S, Konno H, Nakano K, Ninomiya N, Nishio T, Okada M, Plessy C, Shibata K, Shiraki T, Suzuki S, Tagami M, Waki K, Watahiki A, Okamura-Oho Y, Suzuki H, Kawai J, Hayashizaki Y. The transcriptional landscape of the mammalian genome. Science. 2005 Sep 2;309(5740):1559-63. PMID:16141072 doi:309/5740/1559
↑ Guzman RE, Miranda-Laferte E, Franzen A, Fahlke C. Neuronal ClC-3 Splice Variants Differ in Subcellular Localizations, but Mediate Identical Transport Functions. J Biol Chem. 2015 Oct 23;290(43):25851-62. PMID:26342074 doi:10.1074/jbc.M115.668186
↑ Hara-Chikuma M, Yang B, Sonawane ND, Sasaki S, Uchida S, Verkman AS. ClC-3 chloride channels facilitate endosomal acidification and chloride accumulation. J Biol Chem. 2005 Jan 14;280(2):1241-7. PMID:15504734 doi:10.1074/jbc.M407030200
↑ Okada T, Akita T, Sato-Numata K, Islam MR, Okada Y. A newly cloned ClC-3 isoform, ClC-3d, as well as ClC-3a mediates Cd-sensitive outwardly rectifying anion currents. Cell Physiol Biochem. 2014;33(3):539-56. PMID:24603049 doi:10.1159/000358633
↑ Guzman RE, Miranda-Laferte E, Franzen A, Fahlke C. Neuronal ClC-3 Splice Variants Differ in Subcellular Localizations, but Mediate Identical Transport Functions. J Biol Chem. 2015 Oct 23;290(43):25851-62. PMID:26342074 doi:10.1074/jbc.M115.668186
↑ Guzman RE, Bungert-Plümke S, Franzen A, Fahlke C. Preferential association with ClC-3 permits sorting of ClC-4 into endosomal compartments. J Biol Chem. 2017 Nov 17;292(46):19055-19065. PMID:28972156 doi:10.1074/jbc.M117.801951
↑ Guzman RE, Miranda-Laferte E, Franzen A, Fahlke C. Neuronal ClC-3 Splice Variants Differ in Subcellular Localizations, but Mediate Identical Transport Functions. J Biol Chem. 2015 Oct 23;290(43):25851-62. PMID:26342074 doi:10.1074/jbc.M115.668186
↑ Wan Y, Guo S, Zhen W, Xu L, Chen X, Liu F, Shen Y, Liu S, Hu L, Wang X, Ye F, Wang Q, Wen H, Yang F. Structural basis of adenine nucleotides regulation and neurodegenerative pathology in ClC-3 exchanger. Nat Commun. 2024 Aug 6;15(1):6654. PMID:39107281 doi:10.1038/s41467-024-50975-w

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/8jgs"

Categories: Large Structures | Mus musculus | Wan YZQ | Yang F

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 8jgs is ON HOLD  until 2025-08-28
+==Cryo-EM structure of apo state mClC-3_I607T==
+<StructureSection load='8jgs' size='340' side='right'caption='[[8jgs]], [[Resolution|resolution]] 3.96&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[8jgs]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8JGS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8JGS FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.96&#8491;</td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8jgs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8jgs OCA], [https://pdbe.org/8jgs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8jgs RCSB], [https://www.ebi.ac.uk/pdbsum/8jgs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8jgs ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/CLCN3_MOUSE CLCN3_MOUSE] May influence large dense-core vesicle exocytosis in adrenal chromaffin cells.<ref>PMID:16141072</ref>   Strongly outwardly rectifying, electrogenic H(+)/Cl(-)exchanger which mediates the exchange of chloride ions against protons (PubMed:26342074). The CLC channel family contains both chloride channels and proton-coupled anion transporters that exchange chloride or another anion for protons (By similarity). The presence of conserved gating glutamate residues is typical for family members that function as antiporters (By similarity).[UniProtKB:P51790]<ref>PMID:26342074</ref>   Strongly outwardly rectifying, electrogenic H(+)/Cl(-)exchanger which mediates the exchange of chloride ions against protons (PubMed:24603049, PubMed:26342074, PubMed:28972156). Facilitates endosomal acidification and chloride accumulation in hepatocytes (PubMed:15504734).<ref>PMID:15504734</ref> <ref>PMID:24603049</ref> <ref>PMID:26342074</ref> <ref>PMID:28972156</ref>   Strongly outwardly rectifying, electrogenic H(+)/Cl(-)exchanger which mediates the exchange of chloride ions against protons.<ref>PMID:26342074</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+The ClC-3 chloride/proton exchanger is both physiologically and pathologically critical, as it is potentiated by ATP to detect metabolic energy level and point mutations in ClC-3 lead to severe neurodegenerative diseases in human. However, why this exchanger is differentially modulated by ATP, ADP or AMP and how mutations caused gain-of-function remains largely unknow. Here we determine the high-resolution structures of dimeric wildtype ClC-3 in the apo state and in complex with ATP, ADP and AMP, and the disease-causing I607T mutant in the apo and ATP-bounded state by cryo-electron microscopy. In combination with patch-clamp recordings and molecular dynamic simulations, we reveal how the adenine nucleotides binds to ClC-3 and changes in ion occupancy between apo and ATP-bounded state. We further observe I607T mutation induced conformational changes and augments in current. Therefore, our study not only lays the structural basis of adenine nucleotides regulation in ClC-3, but also clearly indicates the target region for drug discovery against ClC-3 mediated neurodegenerative diseases.
-Authors: Wan, Y.Z.Q., Yang, F.
+Structural basis of adenine nucleotides regulation and neurodegenerative pathology in ClC-3 exchanger.,Wan Y, Guo S, Zhen W, Xu L, Chen X, Liu F, Shen Y, Liu S, Hu L, Wang X, Ye F, Wang Q, Wen H, Yang F Nat Commun. 2024 Aug 6;15(1):6654. doi: 10.1038/s41467-024-50975-w. PMID:39107281<ref>PMID:39107281</ref>
-Description: Cryo-EM structure of apo state mClC-3_I607T
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Wan, Y.Z.Q]]
+<div class="pdbe-citations 8jgs" style="background-color:#fffaf0;"></div>
-[[Category: Yang, F]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Large Structures]]
+[[Category: Mus musculus]]
+[[Category: Wan YZQ]]
+[[Category: Yang F]]

8jgs

From Proteopedia

Current revision

Cryo-EM structure of apo state mClC-3_I607T

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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