دورية أكاديمية
أعرض في EDS

Structure of the human K 2P 13.1(THIK-1) channel reveals a novel hydrophilic pore restriction and lipid cofactor site.

التفاصيل البيبلوغرافية
العنوان: Structure of the human K 2P 13.1(THIK-1) channel reveals a novel hydrophilic pore restriction and lipid cofactor site.
المؤلفون: Roy-Chowdhury S; Cardiovascular Research Institute, University of California, San Francisco, California 93858-2330 USA., Jang S; Cardiovascular Research Institute, University of California, San Francisco, California 93858-2330 USA., Abderemane-Ali F; Cardiovascular Research Institute, University of California, San Francisco, California 93858-2330 USA., Naughton F; Cardiovascular Research Institute, University of California, San Francisco, California 93858-2330 USA., Grabe M; Cardiovascular Research Institute, University of California, San Francisco, California 93858-2330 USA.; Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, California 93858-2330 USA., Minor DL Jr; Cardiovascular Research Institute, University of California, San Francisco, California 93858-2330 USA.; Departments of Biochemistry and Biophysics, and Cellular and Molecular Pharmacology, University of California, San Francisco, California 93858-2330 USA.; California Institute for Quantitative Biomedical Research, University of California, San Francisco, California 93858-2330 USA.; Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, California 93858-2330 USA.; Molecular Biophysics and Integrated Bio-imaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720 USA.
المصدر: BioRxiv : the preprint server for biology [bioRxiv] 2024 Jun 27. Date of Electronic Publication: 2024 Jun 27.
نوع المنشور: Journal Article; Preprint
اللغة: English
بيانات الدورية: Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet ISSN: 2692-8205 (Electronic) Linking ISSN: 26928205 NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE
مستخلص: The halothane-inhibited K 2P leak potassium channel K 2P 13.1 (THIK-1) 1-3 is found in diverse cells 1,4 including neurons 1,5 and microglia 6-8 where it affects surveillance6, synaptic pruning7, phagocytosis7, and inflammasome-mediated interleukin-1β release 6,8,9 . As with many K 2P s 1,5,10-14 and other voltage-gated ion channel (VGIC) superfamily members 3,15,16 , polyunsaturated fatty acid (PUFA) lipids modulate K 2P 13.1 (THIK-1) 1,5,14,17 via a poorly understood mechanism. Here, we present cryo-electronmicroscopy (cryo-EM) structures of human K 2P 13.1 (THIK-1) and mutants in lipid nanodiscs and detergent. These reveal that, unlike other K 2P s 13,18-24 , K 2P 13.1 (THIK-1) has a two-chamber aqueous inner cavity obstructed by a M4 transmembrane helix tyrosine (Tyr273, the flow restrictor). This hydrophilic barrier can be opened by an activatory mutation, S136P 25 , at natural break in the M2 transmembrane helix and by intrinsic channel dynamics. The structures also reveal a buried lipid in the P1/M4 intersubunit interface at a location, the PUFA site, that coincides with the TREK subfamily K 2P modulator pocket for small molecule agonists 18,26,27 . This overlap, together with the effects of mutation on K 2P 13.1 (THIK-1) PUFA responses, indicates that the PUFA site lipids are K 2P 13.1 (THIK-1) cofactors. Comparison with the PUFA-responsive VGIC Kv7.1 (KCNQ1) 28-31 reveals a shared role for the equivalent pore domain intersubunit interface in lipid modulation, providing a framework for dissecting the effects of PUFAs on the VGIC superfamily. Our findings reveal the unique architecture underlying K 2P 13.1 (THIK-1) function, highlight the importance of the P1/M4 interface in control of K 2P s by both natural and synthetic agents, and should aid development of THIK subfamily modulators for diseases such as neuroinflammation 6,32 and autism 6 .
Competing Interests: Competing interests The authors declare no competing interests.
References: J Biol Chem. 2001 Mar 9;276(10):7302-11. (PMID: 11060316)
Physiol Rev. 2010 Apr;90(2):559-605. (PMID: 20393194)
Science. 2015 Mar 13;347(6227):1256-9. (PMID: 25766236)
Nature. 2013 Dec 5;504(7478):107-12. (PMID: 24305160)
Elife. 2019 Nov 01;8:. (PMID: 31674909)
J Gen Physiol. 2021 Jun 7;153(6):. (PMID: 33939797)
Protein Sci. 2018 Jan;27(1):293-315. (PMID: 29067766)
Trends Neurosci. 2019 Apr;42(4):278-292. (PMID: 30678990)
Cell Chem Biol. 2024 Jul 18;31(7):1305-1323.e9. (PMID: 39029456)
Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14628-33. (PMID: 19667202)
Structure. 2016 May 3;24(5):797-805. (PMID: 27041595)
J Comput Chem. 2011 Jul 30;32(10):2319-27. (PMID: 21500218)
J Mol Graph. 1996 Dec;14(6):354-60, 376. (PMID: 9195488)
J Biol Chem. 2008 Jul 11;283(28):19448-55. (PMID: 18474599)
Cardiovasc Res. 2018 May 1;114(6):880-893. (PMID: 29360952)
Nat Genet. 2022 Oct;54(10):1534-1543. (PMID: 36195757)
J Protein Chem. 1994 Feb;13(2):195-215. (PMID: 8060493)
J Phys Chem B. 2012 Jun 14;116(23):7006-13. (PMID: 22497303)
Nat Methods. 2017 Mar;14(3):290-296. (PMID: 28165473)
Elife. 2023 May 09;12:. (PMID: 37158595)
Methods Enzymol. 2009;464:211-31. (PMID: 19903557)
Science. 2012 Jan 27;335(6067):436-41. (PMID: 22282805)
Neuron. 2021 Sep 15;109(18):2902-2913.e4. (PMID: 34390650)
Mol Pharmacol. 2020 Aug;98(2):143-155. (PMID: 32616523)
ACS Chem Neurosci. 2018 Dec 19;9(12):3153-3165. (PMID: 30089357)
EMBO J. 1998 Aug 3;17(15):4283-90. (PMID: 9687497)
J Chem Theory Comput. 2016 Jan 12;12(1):405-13. (PMID: 26631602)
Nature. 2014 Dec 4;516(7529):126-30. (PMID: 25471887)
Biochemistry. 1967 Jul;6(7):1948-54. (PMID: 6049437)
Cell. 2020 Jan 23;180(2):340-347.e9. (PMID: 31883792)
Neuron. 2018 Jan 17;97(2):299-312.e6. (PMID: 29290552)
J Gen Physiol. 2018 Dec 3;150(12):1660-1675. (PMID: 30446509)
Glia. 2020 Feb;68(2):328-344. (PMID: 31520551)
Nat Neurosci. 2006 Sep;9(9):1134-41. (PMID: 16906152)
Nat Commun. 2019 Feb 15;10(1):787. (PMID: 30770809)
EMBO J. 2011 Jul 15;30(17):3594-606. (PMID: 21765396)
Cell Rep. 2018 Sep 11;24(11):2908-2918. (PMID: 30208316)
Elife. 2020 Dec 21;9:. (PMID: 33345771)
Acta Crystallogr D Struct Biol. 2018 Jun 1;74(Pt 6):531-544. (PMID: 29872004)
Proc Natl Acad Sci U S A. 2013 Feb 5;110(6):2129-34. (PMID: 23341632)
Trends Biochem Sci. 2024 May;49(5):417-430. (PMID: 38514273)
J Physiol. 2015 Jun 15;593(12):2587-603. (PMID: 25530075)
J Gen Physiol. 2023 Oct 2;155(10):. (PMID: 37526928)
Glia. 2022 Jul;70(7):1301-1316. (PMID: 35353387)
J Physiol. 2021 Feb;599(4):1041-1055. (PMID: 33347640)
Science. 2012 Jan 27;335(6067):432-6. (PMID: 22282804)
Nat Commun. 2013;4:2941. (PMID: 24346231)
Sci Adv. 2020 Oct 30;6(44):. (PMID: 33127683)
Science. 1988 Jun 17;240(4859):1648-52. (PMID: 3381086)
Front Physiol. 2017 Feb 06;8:43. (PMID: 28220076)
J Biol Chem. 2014 Oct 10;289(41):28202-12. (PMID: 25148687)
Nat Chem Biol. 2017 Apr 13;13(5):455-463. (PMID: 28406893)
Sci Adv. 2022 Sep 9;8(36):eabn8785. (PMID: 36070380)
Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501. (PMID: 20383002)
Biochim Biophys Acta. 2016 Nov;1863(11):2766-2783. (PMID: 27566292)
Methods Enzymol. 2021;653:151-188. (PMID: 34099170)
Proc Natl Acad Sci U S A. 2018 Oct 2;115(40):E9459-E9468. (PMID: 30224462)
J Biol Chem. 2002 Feb 15;277(7):5426-32. (PMID: 11733509)
Cell. 2016 Feb 25;164(5):937-49. (PMID: 26919430)
Neuroscience. 2005;135(4):1087-94. (PMID: 16154284)
Acta Crystallogr D Struct Biol. 2019 Oct 1;75(Pt 10):861-877. (PMID: 31588918)
Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):213-21. (PMID: 20124702)
Pflugers Arch. 2014 Jul;466(7):1289-300. (PMID: 24081450)
Neuropharmacology. 2023 Feb 15;224:109330. (PMID: 36375694)
Nat Commun. 2023 Feb 25;14(1):1077. (PMID: 36841877)
Protein Eng. 1995 Feb;8(2):127-34. (PMID: 7630882)
EMBO J. 2011 Aug 05;30(17):3607-19. (PMID: 21822218)
Neuron. 2014 Dec 17;84(6):1198-212. (PMID: 25500157)
Nat Commun. 2022 Jun 9;13(1):3232. (PMID: 35680900)
Nature. 2020 Jun;582(7812):443-447. (PMID: 32499642)
Annu Rev Pharmacol Toxicol. 2021 Jan 6;61:401-420. (PMID: 32679007)
Neuron. 2019 Dec 4;104(5):960-971.e7. (PMID: 31630908)
Immunity. 2018 Jul 17;49(1):56-65.e4. (PMID: 29958799)
J Chem Inf Model. 2011 Oct 24;51(10):2778-86. (PMID: 21919503)
Proc Natl Acad Sci U S A. 2016 Apr 12;113(15):4194-9. (PMID: 27035963)
EMBO J. 2006 Jun 7;25(11):2368-76. (PMID: 16675954)
Proc Natl Acad Sci U S A. 2021 Oct 19;118(42):. (PMID: 34642249)
Proc Natl Acad Sci U S A. 2004 Jan 27;101(4):959-63. (PMID: 14732697)
J Mol Biol. 2021 Aug 20;433(17):166995. (PMID: 33887333)
J Biol Chem. 2013 Dec 6;288(49):35081-92. (PMID: 24163367)
EMBO J. 2012 Aug 1;31(15):3297-308. (PMID: 22728824)
Nature. 2020 Oct;586(7829):457-462. (PMID: 32999458)
Proc Natl Acad Sci U S A. 2014 Mar 4;111(9):3614-9. (PMID: 24550493)
Cell Chem Biol. 2020 May 21;27(5):511-524.e4. (PMID: 32059793)
Nat Protoc. 2014 Nov;9(11):2574-85. (PMID: 25299155)
Nat Methods. 2017 Jan;14(1):71-73. (PMID: 27819658)
Pflugers Arch. 2014 Sep;466(9):1735-45. (PMID: 24297522)
J Med Chem. 2017 Feb 9;60(3):1076-1088. (PMID: 28051863)
J Comput Chem. 2014 Oct 15;35(27):1997-2004. (PMID: 25130509)
J Neurosci. 2010 Jul 7;30(27):9324-34. (PMID: 20610767)
EMBO J. 1998 Jun 15;17(12):3297-308. (PMID: 9628867)
Proc Natl Acad Sci U S A. 2011 Jul 26;108(30):12313-8. (PMID: 21746903)
Nature. 2017 Jul 20;547(7663):364-368. (PMID: 28693035)
Neuron. 2019 Jan 16;101(2):232-245.e6. (PMID: 30573346)
Proc Natl Acad Sci U S A. 2016 Apr 12;113(15):4200-5. (PMID: 27035965)
Neuroscience. 2008 Feb 19;151(4):1154-72. (PMID: 18222039)
معلومات مُعتمدة: R01 MH093603 United States MH NIMH NIH HHS
فهرسة مساهمة: Keywords: K2P channel; cryo-electronmicroscopy; electrophysiology; lipid nanodiscs; polyunsaturated fatty acid (PUFA)
تواريخ الأحداث: Date Created: 20240709 Latest Revision: 20240721
رمز التحديث: 20240721
مُعرف محوري في PubMed: PMC11230452
DOI: 10.1101/2024.06.26.600491
PMID: 38979306
قاعدة البيانات: MEDLINE
الوصف
تدمد:2692-8205
DOI:10.1101/2024.06.26.600491