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Title: TrkA undergoes a tetramer-to-dimer conversion to open TrkH which enables changes in membrane potential

Abstract

TrkH is a bacterial ion channel implicated in K+ uptake and pH regulation. TrkH assembles with its regulatory protein, TrkA, which closes the channel when bound to ADP and opens it when bound to ATP. However, it is unknown how nucleotides control the gating of TrkH through TrkA. Here we report the structures of the TrkH-TrkA complex in the presence of ADP or ATP. TrkA forms a tetrameric ring when bound to ADP and constrains TrkH to a closed conformation. The TrkA ring splits into two TrkA dimers in the presence of ATP and releases the constraints on TrkH, resulting in an open channel conformation. Functional studies show that both the tetramer-to-dimer conversion of TrkA and the loss of constraints on TrkH are required for channel gating. In addition, deletion of TrkA in Escherichia coli depolarizes the cell, suggesting that the TrkH-TrkA complex couples changes in intracellular nucleotides to membrane potential.

Authors:
 [1];  [1]; ORCiD logo [1];  [2];  [2];  [1];  [1]; ORCiD logo [1]; ORCiD logo [1];  [2];  [3];  [1]
  1. Baylor College of Medicine, Houston, TX (United States)
  2. Texas A & M Univ., College Station, TX (United States)
  3. Stanford Univ., CA (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH); Cancer Prevention and Research Institute of Texas (CPRIT); Robert Welch Foundation
OSTI Identifier:
1598012
Grant/Contract Number:  
HL086392; DK122784; P41GM103832; GM132436; R1223; Q-1279; Q-1967; A-1742; AC02-06CH11357
Resource Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 11; Journal Issue: 1; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH
Subject:
36 MATERIALS SCIENCE; Cryoelectron microscopy; Permeation and transport; X-ray crystallography

Citation Formats

Zhang, Hanzhi, Pan, Yaping, Hu, Liya, Hudson, M. Ashley, Hofstetter, Katrina S., Xu, Zhichun, Rong, Mingqiang, Wang, Zhao, Prasad, B. V. Venkataram, Lockless, Steve W., Chiu, Wah, and Zhou, Ming. TrkA undergoes a tetramer-to-dimer conversion to open TrkH which enables changes in membrane potential. United States: N. p., 2020. Web. https://doi.org/10.1038/s41467-019-14240-9.
Zhang, Hanzhi, Pan, Yaping, Hu, Liya, Hudson, M. Ashley, Hofstetter, Katrina S., Xu, Zhichun, Rong, Mingqiang, Wang, Zhao, Prasad, B. V. Venkataram, Lockless, Steve W., Chiu, Wah, & Zhou, Ming. TrkA undergoes a tetramer-to-dimer conversion to open TrkH which enables changes in membrane potential. United States. https://doi.org/10.1038/s41467-019-14240-9
Zhang, Hanzhi, Pan, Yaping, Hu, Liya, Hudson, M. Ashley, Hofstetter, Katrina S., Xu, Zhichun, Rong, Mingqiang, Wang, Zhao, Prasad, B. V. Venkataram, Lockless, Steve W., Chiu, Wah, and Zhou, Ming. Tue . "TrkA undergoes a tetramer-to-dimer conversion to open TrkH which enables changes in membrane potential". United States. https://doi.org/10.1038/s41467-019-14240-9. https://www.osti.gov/servlets/purl/1598012.
@article{osti_1598012,
title = {TrkA undergoes a tetramer-to-dimer conversion to open TrkH which enables changes in membrane potential},
author = {Zhang, Hanzhi and Pan, Yaping and Hu, Liya and Hudson, M. Ashley and Hofstetter, Katrina S. and Xu, Zhichun and Rong, Mingqiang and Wang, Zhao and Prasad, B. V. Venkataram and Lockless, Steve W. and Chiu, Wah and Zhou, Ming},
abstractNote = {TrkH is a bacterial ion channel implicated in K+ uptake and pH regulation. TrkH assembles with its regulatory protein, TrkA, which closes the channel when bound to ADP and opens it when bound to ATP. However, it is unknown how nucleotides control the gating of TrkH through TrkA. Here we report the structures of the TrkH-TrkA complex in the presence of ADP or ATP. TrkA forms a tetrameric ring when bound to ADP and constrains TrkH to a closed conformation. The TrkA ring splits into two TrkA dimers in the presence of ATP and releases the constraints on TrkH, resulting in an open channel conformation. Functional studies show that both the tetramer-to-dimer conversion of TrkA and the loss of constraints on TrkH are required for channel gating. In addition, deletion of TrkA in Escherichia coli depolarizes the cell, suggesting that the TrkH-TrkA complex couples changes in intracellular nucleotides to membrane potential.},
doi = {10.1038/s41467-019-14240-9},
journal = {Nature Communications},
number = 1,
volume = 11,
place = {United States},
year = {2020},
month = {1}
}

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Works referenced in this record:

Structure and transport mechanism of a high-affinity potassium uptake transporter from higher plants
journal, August 1994

  • Schachtman, Daniel P.; Schroeder, Julian I.
  • Nature, Vol. 370, Issue 6491
  • DOI: 10.1038/370655a0

Two systems mediate rubidium uptake in Neurospora crassa: one exhibits the dual-uptake isotherm
journal, May 1986

  • Rodríguez-Navarro, Alonso; Ramos, José
  • Biochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 857, Issue 2
  • DOI: 10.1016/0005-2736(86)90351-2

Ion channels enable electrical communication in bacterial communities
journal, October 2015

  • Prindle, Arthur; Liu, Jintao; Asally, Munehiro
  • Nature, Vol. 527, Issue 7576
  • DOI: 10.1038/nature15709

The bacterial flagellar motor and its structural diversity
journal, May 2015


Cloning of the trkAH gene cluster and characterization of the Trk K+-uptake system of Vibrio alginolyticus
journal, August 1998


Osmotic stress response in C. glutamicum: impact of channel- and transporter-mediated potassium accumulation
journal, May 2011

  • Ochrombel, Ines; Becker, Markus; Krämer, Reinhard
  • Archives of Microbiology, Vol. 193, Issue 11
  • DOI: 10.1007/s00203-011-0717-6

Overview of the CCP 4 suite and current developments
journal, March 2011

  • Winn, Martyn D.; Ballard, Charles C.; Cowtan, Kevin D.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4
  • DOI: 10.1107/S0907444910045749

The RCK Domain of the KtrAB K+ Transporter: Multiple Conformations of an Octameric Ring
journal, September 2006


Quantitative measurements of membrane potential in Escherichia coli
journal, July 1980

  • Felle, H.; Porter, J. S.; Slayman, C. L.
  • Biochemistry, Vol. 19, Issue 15
  • DOI: 10.1021/bi00556a026

Na + -dependent K + Uptake Ktr System from the Cyanobacterium Synechocystis sp. PCC 6803 and Its Role in the Early Phases of Cell Adaptation to Hyperosmotic Shock
journal, September 2004

  • Matsuda, Nobuyuki; Kobayashi, Hiroshi; Katoh, Hirokazu
  • Journal of Biological Chemistry, Vol. 279, Issue 52
  • DOI: 10.1074/jbc.M407268200

Electron counting and beam-induced motion correction enable near-atomic-resolution single-particle cryo-EM
journal, May 2013

  • Li, Xueming; Mooney, Paul; Zheng, Shawn
  • Nature Methods, Vol. 10, Issue 6
  • DOI: 10.1038/nmeth.2472

Effects of potassium ions on the electrical and pH gradients across the membrane of Streptococcus lactis cells.
journal, January 1977


Production of giant cells of Escherichia coli.
journal, January 1978


Accurate model annotation of a near-atomic resolution cryo-EM map
journal, March 2017

  • Hryc, Corey F.; Chen, Dong-Hua; Afonine, Pavel V.
  • Proceedings of the National Academy of Sciences, Vol. 114, Issue 12
  • DOI: 10.1073/pnas.1621152114

Impact of transport processes in the osmotic response of Corynebacterium glutamicum
journal, September 2003


Structure of the Human BK Channel Ca2+-Activation Apparatus at 3.0 A Resolution
journal, May 2010


CTFFIND4: Fast and accurate defocus estimation from electron micrographs
journal, November 2015


The K+ uptake regulator TrkA controls membrane potential, pH homeostasis and multidrug susceptibility in Mycobacterium smegmatis
journal, May 2011

  • Castaneda-Garcia, A.; Do, T. T.; Blazquez, J.
  • Journal of Antimicrobial Chemotherapy, Vol. 66, Issue 7
  • DOI: 10.1093/jac/dkr165

Interconversion of components of the bacterial proton motive force by electrogenic potassium transport.
journal, January 1981


Potassium Transport Loci in Escherichia coli K-12
journal, January 1971


Evolutionary Relationship between K+ Channels and Symporters
journal, August 1999


KtrAB, a New Type of Bacterial K+-Uptake System from Vibrio alginolyticus
journal, January 1998


The structure of the KtrAB potassium transporter
journal, April 2013

  • Vieira-Pires, Ricardo S.; Szollosi, Andras; Morais-Cabral, João H.
  • Nature, Vol. 496, Issue 7445
  • DOI: 10.1038/nature12055

Real-space refinement in PHENIX for cryo-EM and crystallography
journal, May 2018

  • Afonine, Pavel V.; Poon, Billy K.; Read, Randy J.
  • Acta Crystallographica Section D Structural Biology, Vol. 74, Issue 6
  • DOI: 10.1107/S2059798318006551

SerialEM: A Program for Automated Tilt Series Acquisition on Tecnai Microscopes Using Prediction of Specimen Position
journal, July 2003


LigPlot+: Multiple Ligand–Protein Interaction Diagrams for Drug Discovery
journal, October 2011

  • Laskowski, Roman A.; Swindells, Mark B.
  • Journal of Chemical Information and Modeling, Vol. 51, Issue 10
  • DOI: 10.1021/ci200227u

Helical jackknives control the gates of the double-pore K+ uptake system KtrAB
journal, May 2017

  • Diskowski, Marina; Mehdipour, Ahmad Reza; Wunnicke, Dorith
  • eLife, Vol. 6
  • DOI: 10.7554/eLife.24303

UCSF Chimera?A visualization system for exploratory research and analysis
journal, January 2004

  • Pettersen, Eric F.; Goddard, Thomas D.; Huang, Conrad C.
  • Journal of Computational Chemistry, Vol. 25, Issue 13
  • DOI: 10.1002/jcc.20084

Potassium ion is required for the generation of pH-dependent membrane potential and .DELTA.pH by the marine bacterium Vibrio alginolyticus
journal, July 1981

  • Tokuda, Hajime; Nakamura, Tatsunosuke; Unemoto, Tsutomu
  • Biochemistry, Vol. 20, Issue 14
  • DOI: 10.1021/bi00517a038

Impact of improved potassium accumulation on pH homeostasis, membrane potential adjustment and survival of Corynebacterium glutamicum
journal, April 2011

  • Ochrombel, Ines; Ott, Lisa; Krämer, Reinhard
  • Biochimica et Biophysica Acta (BBA) - Bioenergetics, Vol. 1807, Issue 4
  • DOI: 10.1016/j.bbabio.2011.01.008

Improved low-resolution crystallographic refinement with Phenix and Rosetta
journal, September 2013

  • DiMaio, Frank; Echols, Nathaniel; Headd, Jeffrey J.
  • Nature Methods, Vol. 10, Issue 11
  • DOI: 10.1038/nmeth.2648

Strength of Selection Pressure Is an Important Parameter Contributing to the Complexity of Antibiotic Resistance Evolution
journal, June 2014

  • Oz, Tugce; Guvenek, Aysegul; Yildiz, Sadik
  • Molecular Biology and Evolution, Vol. 31, Issue 9
  • DOI: 10.1093/molbev/msu191

EMAN2: An extensible image processing suite for electron microscopy
journal, January 2007

  • Tang, Guang; Peng, Liwei; Baldwin, Philip R.
  • Journal of Structural Biology, Vol. 157, Issue 1
  • DOI: 10.1016/j.jsb.2006.05.009

Cloned Potassium Channels from Eukaryotes and Prokaryotes
journal, March 1997


Gating of the TrkH ion channel by its associated RCK protein TrkA
journal, April 2013


Coot model-building tools for molecular graphics
journal, November 2004

  • Emsley, Paul; Cowtan, Kevin
  • Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132
  • DOI: 10.1107/S0907444904019158

RELION: Implementation of a Bayesian approach to cryo-EM structure determination
journal, December 2012


Electrically induced bacterial membrane-potential dynamics correspond to cellular proliferation capacity
journal, April 2019

  • Stratford, James P.; Edwards, Conor L. A.; Ghanshyam, Manjari J.
  • Proceedings of the National Academy of Sciences, Vol. 116, Issue 19
  • DOI: 10.1073/pnas.1901788116

TRK1 encodes a plasma membrane protein required for high-affinity potassium transport in Saccharomyces cerevisiae.
journal, July 1988

  • Gaber, R. F.; Styles, C. A.; Fink, G. R.
  • Molecular and Cellular Biology, Vol. 8, Issue 7
  • DOI: 10.1128/MCB.8.7.2848

PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010

  • Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221
  • DOI: 10.1107/S0907444909052925

Crystal structure of the potassium-importing KdpFABC membrane complex
journal, June 2017

  • Huang, Ching-Shin; Pedersen, Bjørn Panyella; Stokes, David L.
  • Nature, Vol. 546, Issue 7660
  • DOI: 10.1038/nature22970

Crystal structure of a potassium ion transporter, TrkH
journal, February 2011


Bacterial evolution of antibiotic hypersensitivity
journal, January 2013

  • Lázár, Viktória; Pal Singh, Gajinder; Spohn, Réka
  • Molecular Systems Biology, Vol. 9, Issue 1
  • DOI: 10.1038/msb.2013.57

Potassium and sodium transport in non-animal cells: the Trk/Ktr/HKT transporter family
journal, March 2010

  • Corratgé-Faillie, C.; Jabnoune, M.; Zimmermann, S.
  • Cellular and Molecular Life Sciences, Vol. 67, Issue 15
  • DOI: 10.1007/s00018-010-0317-7

Patch Clamp and Phenotypic Analyses of a Prokaryotic Cyclic Nucleotide-gated K + Channel Using Escherichia coli as a Host
journal, June 2007

  • Kuo, Mario Meng-Chiang; Saimi, Yoshiro; Kung, Ching
  • Journal of Biological Chemistry, Vol. 282, Issue 33
  • DOI: 10.1074/jbc.M703618200

Crystal structure and mechanism of a calcium-gated potassium channel
journal, May 2002

  • Jiang, Youxing; Lee, Alice; Chen, Jiayun
  • Nature, Vol. 417, Issue 6888
  • DOI: 10.1038/417515a

Structure of the RCK Domain from the E. coli K+ Channel and Demonstration of Its Presence in the Human BK Channel
journal, March 2001


A rapid microtiter plate assay for measuring the effect of compounds on Staphylococcus aureus membrane potential
journal, November 2010

  • Gentry, Daniel R.; Wilding, Imogen; Johnson, John M.
  • Journal of Microbiological Methods, Vol. 83, Issue 2
  • DOI: 10.1016/j.mimet.2010.08.012

Evolution of high-level resistance during low-level antibiotic exposure
journal, April 2018


ConSurf 2016: an improved methodology to estimate and visualize evolutionary conservation in macromolecules
journal, May 2016

  • Ashkenazy, Haim; Abadi, Shiran; Martz, Eric
  • Nucleic Acids Research, Vol. 44, Issue W1
  • DOI: 10.1093/nar/gkw408

RosettaScripts: A Scripting Language Interface to the Rosetta Macromolecular Modeling Suite
journal, June 2011


[20] Processing of X-ray diffraction data collected in oscillation mode
book, January 1997