Vladimir Yarov-Yarovoy

image of Vladimir Yarov-Yarovoy

Associate Professor

Departments

Biochemistry and Molecular Medicine
Anesthesiology & Pain Medicine
Physiology and Membrane Biology

Offices and Labs

Tupper Hall, Room 4131, Davis, CA 95616
+1 530 752 5298

Degrees

2003 Postdoc Computational Biology University of Washington
1998 Ph.D. Biophysics Oregon Health Science University
1993 M.S. Biophysics Moscow State University

Research Interests

My research interests and expertise encompass neuroscience, protein structure, computational biology, and evolution. Main focus of my research group is on structure and function studies of voltage-gated ion channels, computational design and chemical synthesis of subtype-specific modulators of voltage-gated ion channels, development of computational methods for membrane protein structure prediction and design, and analysis of evolution of human voltage-gated ion channels.

Structure-Function of Voltage-Gated Sodium Channels

Function and modulation of neuronal sodium channels are critical for the neuromodulation of electrical excitability and synaptic transmission in neurons - the basis for many aspects of signal transduction, learning, memory and physiological regulation. Mutations in neuronal voltage-gated sodium channel genes are responsible for various human neurological disorders. Furthermore, human neuronal voltage-gated sodium channels are primary targets of therapeutic drugs used as local anesthetics and for treatment of neurological and cardiac disorders. My first project is focusing on studying of neuronal voltage-gated sodium channels structure, function, and modulation in order to design new therapeutically useful drugs for treatment of pain and epilepsy. Serious, chronic pain affects at least 116 million Americans each year and epilepsy affects nearly 3 million Americans and 50 million people Worldwide. However, the treatment of chronic pain and epilepsy remains a major unmet medical need because the use of currently available drugs is limited due to incomplete efficacy and/or significant side effects. Considerable efforts by pharmaceutical industry toward identifying selective inhibitors of one or more of Nav channel subtypes did not generate any genuinely subtype selective blockers and none are currently advancing through clinical trials. My laboratory uses an innovative approach to design novel subtype selective Nav channel blocking drugs with high efficacy and minimum side effects. Novel drugs will be tested using methods of electrophysiology, biochemistry, and molecular biology. This project will provide key structural information on the molecular basis of neuronal voltage-gated sodium channels function and its interaction with therapeutically useful subtype-specific modulators. Understanding of function and modulation of the neuronal voltage-gated sodium channels on structural level will give us profound insights into the fundamental mechanisms underlying neuromodulation and signal transduction.

Protein Design

Over the past decade, there has been significant progress in determining membrane protein structures in general and ion channel structures in particular using x-ray crystallography methods. However, it is still very difficult to obtain high-resolution structural information about these proteins. My second project is focusing on further development of the Rosetta-Membrane computational method for high-resolution membrane protein structure prediction and design. I developed the original Rosetta-Membrane method for membrane protein structure prediction in collaboration with David Baker's group at the University of Washington and applied it for modeling of membrane proteins in general and ion channels in particular. I now propose to further improve accuracy of the Rosetta-Membrane method and expand its capabilities to design membrane proteins with new functions.

Ion Channel Evolution

Evolution of ion channels from bacteria to human took several billion years and while there are basic features that are common to bacterial and human ion channels, such as pore-forming and/or voltage-sensing domains, there are abundance of unique features in every human ion channel family that are absent in bacterial ion channels and have been designed through evolutionary time to accomplish highly specific functions. My third project is focusing on exploring evolution of human voltage-gated ion channels using available prokaryotic and eukaryotic genomes and high-resolution ion channels structures. Human ion channel family is ranking third in a number of family members after the G protein coupled receptors and the protein kinases. To identify the mechanisms by which historical mutations generated distinct human ion channel functions, it is essential to compare proteins through evolutionary time. Moreover, reconstruction of key intermediate ancestors of ion channels by computational structural design can further advance our understanding of evolution of human ion channel function. Previously, I used bioinformatics based analysis of available high-resolution membrane proteins structures to derive parameters of membrane environment-specific scoring function used in the Rosetta-Membrane method. I now propose to analyze evolution of human voltage-gated sodium channels using phylogenetic trees and multiple sequence alignments of homologous sequences and correlate it with available structural and functional data. I will use the Rosetta-Membrane method to predict structures of human ion channels for which high-resolution structures are not available. Mapping of evolutionary information onto human voltage-gated sodium channel structures will give us significant new insights into evolution of their structure and function.

Collaborators at UC Davis

Department of Anesthesiology and Pain Medicine: Scott Fishman

Department of Biochemistry and Molecular Medicine: Kit Lam, Justin Siegel, Lin Tian, and John Voss

Department of Biomedical Engineering: Marc Facciotti

Department of Cell Biology and Human Anatomy: Paul Fitzgerald

Department of Internal Medicine: Nipavan Chiamvimonvat

Department of Molecular and Cellular Biology: Jonathan Scholey

Department of Neurobiology, Physiology and Behavior: James Trimmer

Department of Pharmacology: Donald Bers, Colleen Clancy, Elva Diaz, and Heike Wulff

Department of Physiology and Membrane Biology: Pete Cala, Michel Ferns, Alla Fomina, Jon Sack, and Jie Zheng

Collaborators outside of UC Davis

City College of New York: Themis Lazaridis

Johns Hopkins University: Mark Donowitz and Jeff Gray

National Institutes of Health: Kenton Swartz

Royal Melbourne Institute of Technology (Australia): Toby Allen

Stanford University: Justin Du Bois

University of Calgary (Canada): Sergei Noskov

University of California Berkeley: Ehud Isacoff

University of California San Francisco: Bill DeGrado and Daniel Minor

University of Chicago: Benoit Roux

University of Copenhagen (Denmark): Stine Pedersen

University of Innsbruck (Austria): Bernhard Flucher and Joerg Striessnig

University of Utah: Baldomero Olivera

University of Washington: David Baker, William Catterall, and Allan Rettie

Vanderbilt University: Jens Meiler

Weizmann Institute of Science (Israel): Sarel Fleishman

Awards

National Institutes of Health Career Development Award
University of Washington Royalty Research Fund Award
University of California Davis Academic Senate Faculty Research Grant Award

ProfessionalSocieties

Biophysical Society
American Pain Society

CBS Grad Group Affiliations

Molecular, Cellular, and Integrative Physiology
Biophysics

Specialties / Focus

Molecular, Cellular, and Integrative Physiology
  • Cellular Physiology
  • Molecular Physiology
  • Neurophysiology

Labs

  • Drew Tilley (PhD student, co-mentored with Jon Sack)
  • Phuong Tran (PhD student, co-mentored with Toby Allen)
  • Ian Kimball (PhD student, co-mentored with Jon Sack)
  • Kevin DeMarco (PhD student, co-mentored with Colleen Clancy)
  • Fan Yang (Postdoc, co-mentored with Jie Zheng)
  • Diane Nguyen (undergraduate student)
  • Cierra Joseph (undergraduate student)
  • Jan Maly (PhD student)
  • Aiyana Emigh (PhD student, co-mentored with Igor Vorobyov)

Courses

Biophys. BPH200B Techniques in Biophysics (Spring)
Neurosci. NEU420-PHA400B Clinical Neurosciences/ Pharmacology (Summer)
Biochem. MCB/BPH 241 Membrane Biology (Spring)
Physiol. HPH400 Human Physiology (Fall)
Physiol. MCP210A Advanced Physiology (Fall)

Personal Interests

Contemporary Art website
Classical Music website
Contemporary Ballet website
Skiing website
Trans Music website
interactive 3D environment website
Wine Country website
Contemporary Jazz website

Publications

1/10/2017 11:20:39 AM
  • Yang F, Vu S, Yarov-Yarovoy V, Zheng J (2016) Rational design and validation of a vanilloid-sensitive TRPV2 ion channel. Proc Natl Acad Sci U S A 113, E3657-66.

  • Tuluc P*, Yarov-Yarovoy V*, Benedetti B, Flucher BE (2016) Molecular Interactions in the Voltage Sensor Controlling Gating Properties of Cav Calcium Channels. Structure 24, 261-71.

  • Kaur I, Yarov-Yarovoy V, Kirk LM, Plambeck KE, Barragan EV, Ontiveros ES, Díaz E (2016) Activity-Dependent Palmitoylation Controls SynDIG1 Stability, Localization, and Function. J Neurosci. 36, 7562-8.

  • Becker EA, Yao AI, Seitzer PM, Kind T, Wang T, Eigenheer R, Shao KS, Yarov-Yarovoy V, Facciotti MT (2016) A Large and Phylogenetically Diverse Class of Type 1 Opsins Lacking a Canonical Retinal Binding Site. PLoS One 11, e0156543.

  • Sihn CR, Kim HJ, Woltz RL, Yarov-Yarovoy V, Yang PC, Xu J, Clancy CE, Zhang XD, Chiamvimonvat N, Yamoah EN (2016) Mechanisms of Calmodulin Regulation of Different Isoforms of Kv7.4 K+ Channels. J. Biol. Chem. 291, 2499-509.

  • Yang S, Yang F, Xiao X, Wei N, Hong J, Li B, Luo L, Rong M, Yarov-Yarovoy V, Zheng J, Wang K, Lai R (2015) A Pain-Inducing Centipede Toxin Targets the Heat Activation Machinery of Nociceptor TRPV1. Nat Commun. 6, 8297.

  • Kaur G, Pinggera A, Ortner NJ, Lieb A, Sinnegger-Brauns MJ, Yarov-Yarovoy V, Obermair GJ, Flucher BE, Striessnig J (2015) A Polybasic Plasma Membrane Binding Motif in the I-II Linker Stabilizes Voltage-Gated Cav1.2 Calcium Channel Function. J. Biol. Chem., 290, 21086-100.

  • Yang F, Xiao X, Cheng W, Yang W, Yu P, Song Z, Yarov-Yarovoy V, Zheng J (2015) Structural mechanism underlying capsaicin binding and activation of nociceptive TRPV1 ion channel. Nat Chem Biol. 11, 518-24.

  • Gupta K, Zamanian M, Bae C, Milescu M, Krepkiy D, Tilley DC, Sack JT, Yarov-Yarovoy V, Kim JI, Swartz KJ (2015) Tarantula toxins use common surfaces for interacting with Kv and ASIC ion channels. eLife 4, e06774.

  • Chen-Izu Y, Shaw RM, Pitt GS, Yarov-Yarovoy V, Sack JT, Abriel H, Aldrich RW, Belardinelli L, Cannell MB, Catterall WA, Chazin WJ, Chiamvimonvat N, Deschenes I, Grandi E, Hund TJ, Izu LT, Maier LS, Maltsev VA, Marionneau C, Mohler PJ, Rajamani S, Rasmusson RL, Sobie EA, Clancy CE, Bers DM (2015) Na+ channel function, regulation, structure, trafficking and sequestration. J Physiol. 593,1347-60.

  • Yarov-Yarovoy V, Allen TW, and Clancy CE. (2014) Computational Models for Predictive Ion Channel Pharmacology. Drug Discovery Today: Disease Models, 14, 3-10.

  • Yarov-Yarovoy V. (2014) Rosetta Structural Modeling, Zheng J, Trudeau M, (ed), Handbook of Ion Channels, CRC Press, Boca Raton.

  • Tilley DC, Eum KS, Fletcher-Taylor S, Austin DC, Dupré C, Patrón L, Garcia R, Lam K, Yarov-Yarovoy V, Cohen BE, and Sack JT. (2014) Chemoselective tarantula toxins report voltage activation of wild-type ion channels in live cells. PNAS, 111: E4789-96.

  • Boiteux C, Vorobyov I, French RJ, French C, Yarov-Yarovoy V and Allen TW. (2014) Local anesthetic and anti-epileptic drug access and binding to a bacterial voltage-gated sodium channel. PNAS, 111:13057-62.

  • Rafizadeh S, Zhang Z, Woltz RL, Kim HJ, Myers RE, Lu L, Tuteja D, Singapuri A, Bigdeli AAZ, Harchache SB, Knowlton AA, Yarov-Yarovoy V, Yamoah EN, and Chiamvimonvat N. (2014) Functional interaction with filamin A enhances the surface membrane expression of a small-conductance Ca2+ -activated K+ (SK2) channel. PNAS, 111: 9989-9994.

  • Wulff H and Yarov-Yarovoy V (2013) Channels: Sticking to nooks and crannies. Nat Chem Biol. 9, 473-4.

  • Acar S, Carlson D, Budamagunta M, Yarov-Yarovoy V, Correia JJ, Niñonuevo MR, Jia W, Tao L, Leary JA, Voss J, Evans JE, Scholey JM (2013) The Bipolar Assembly Domain of the Mitotic Motor Kinesin-5. Nat Commun 4, 1343.

  • Timofeyev V, Myers RE, Kim HJ, Woltz RL, Sirish P, Heiserman JP, Li N, Singapuri A, Tang T, Yarov-Yarovoy V, Yamoah EN, Hammond HK, and Chiamvimonvat N (2013) Adenylyl Cyclase Subtype–Specific Compartmentalization Differential Regulation of L-Type Ca2+ Current in Ventricular Myocytes. Circulation Res. 112, 1567-76.

  • Vargas E, Yarov-Yarovoy V, Khalili-Aragi F, Catterall WA, Klein ML, Tarek M, Lindahl E, Schulten K, Perozo E, Bezanilla F, and Roux B (2012) An emerging consensus on voltage-dependent gating from computational modeling and molecular dynamics simulations. J Gen Physiol 140, 587-94.

  • Khafagaa M, Bossuyt J, Mamikoniana L, Lia JC, Lee LL, Yarov-Yarovoy V, Despa S, and Bers DM (2012) Na+/K+-ATPase E960 and Phospholemman F28 are critical for their functional interaction. PNAS 109, 20756-61.

  • Yarov-Yarovoy V, DeCaen PG, Westenbroek, RE, Pan C-Y, Scheuer T, Baker D, and Catterall WA (2012) Structural Basis for Gating Charge Movement in the Voltage Sensor of a Sodium Channel. PNAS 109, E93-102.

  • Yarov-Yarovoy, V (2012) Toxin-Channel Interactions in K Channels. Encyclopedia of Metalloproteins. Springer Science.

  • Zhang JZ, Yarov-Yarovoy V, Scheuer T, Karbat I, Cohen L, Gordon D, Gurevitz M, and Catterall WA (2012) Mapping the interaction site for a β-scorpion toxin in the pore module of domain III of voltage-gated sodium channels. J. Biol. Chem. 287, 30719-28.

  • Watschinger K, Fuchs JE, Yarov-Yarovoy V, Keller MA, Golderer G, Hermetter A, Werner-Felmayer G, Hulo N, Werner ER (2012) Biochem J. 443, 279-86.
  • Cui Y, Yang F, Cao X, Yarov-Yarovoy V, Wang K, Zheng J. (2012) Selective disruption of high sensitivity heat activation but not capsaicin activation of TRPV1 channels by pore turret mutations. J Gen Physiol, 139, 273-83.
  • Oganesian A, Yarov-Yarovoy V, Parks WC, and Schwinn DA (2011) Constitutive coupling of a naturally occurring human alpha1a-adrenergic receptor genetic variant to EGFR transactivation pathway. PNAS 108, 19796-19801.
  • DeCaen PG, Yarov-Yarovoy V, Scheuer T, and Catterall WA (2011) Gating Charge Interactions with the S1 Segment During Activation of a Na+ Channel Voltage Sensor. PNAS 108, 18825-18830.
  • Zhang JZ, Yarov-Yarovoy V, Scheuer T, Karbat I, Cohen L, Gordon D, Gurevitz M, Catterall WA (Sep 2011) Structure-Function Map of the Receptor Site for {beta}-Scorpion Toxins in Domain II of Voltage-gated Sodium Channels., The Journal of Biological Chemistry, 286 (38), 33641-51
  • Wang J, Yarov-Yarovoy V, Kahn R, Gordon D, Gurevitz M, Scheuer T, Catterall WA (Sep 2011) Mapping the receptor site for {alpha}-scorpion toxins on a Na+ channel voltage sensor., Proceedings of the National Academy of Sciences of the United States of America, 108 (37), 15426-31
  • Subbotina J, Yarov-Yarovoy V, Lees-Miller J, Durdagi S, Guo J, Duff HJ, Noskov SY (Nov 2010) Structural refinement of the hERG1 pore and voltage-sensing domains with ROSETTA-membrane and molecular dynamics simulations., Proteins, 78 (14), 2922-34
  • Khalili-Araghi F, Jogini V, Yarov-Yarovoy V, Tajkhorshid E, Roux B, Schulten K (May 2010) Calculation of the gating charge for the Kv1.2 voltage-activated potassium channel., Biophysical journal, 98 (10), 2189-98
  • Catterall WA, Yarov-Yarovoy V (2010) Helical motion of an S4 voltage sensor revealed by gating pore currents., Channels (Austin, Tex.), 4 (2), 75-7
  • DeCaen PG, Yarov-Yarovoy V, Sharp EM, Scheuer T, Catterall WA (Dec 2009) Sequential formation of ion pairs during activation of a sodium channel voltage sensor., Proceedings of the National Academy of Sciences of the United States of America, 106 (52), 22498-503
  • DeCaen PG, Yarov-Yarovoy V, Zhao Y, Scheuer T, Catterall WA (Sep 2008) Disulfide locking a sodium channel voltage sensor reveals ion pair formation during activation., Proceedings of the National Academy of Sciences of the United States of America, 105 (39), 15142-7
  • Pathak MM, Yarov-Yarovoy V, Agarwal G, Roux B, Barth P, Kohout S, Tombola F, Isacoff EY (Oct 2007) Closing in on the resting state of the Shaker K(+) channel., Neuron, 56 (1), 124-40
  • Catterall WA, Cestèle S, Yarov-Yarovoy V, Yu FH, Konoki K, Scheuer T (Feb 2007) Voltage-gated ion channels and gating modifier toxins., Toxicon : official journal of the International Society on Toxinology, 49 (2), 124-41
  • Hulme JT, Yarov-Yarovoy V, Lin TW, Scheuer T, Catterall WA (Oct 2006) Autoinhibitory control of the CaV1.2 channel by its proteolytically processed distal C-terminal domain., The Journal of physiology, 576 (Pt 1), 87-102
  • Cestèle S, Yarov-Yarovoy V, Qu Y, Sampieri F, Scheuer T, Catterall WA (Jul 2006) Structure and function of the voltage sensor of sodium channels probed by a beta-scorpion toxin., The Journal of biological chemistry, 281 (30), 21332-44
  • Yarov-Yarovoy V, Baker D, Catterall WA (May 2006) Voltage sensor conformations in the open and closed states in ROSETTA structural models of K(+) channels., Proceedings of the National Academy of Sciences of the United States of America, 103 (19), 7292-7
  • Yarov-Yarovoy V, Schonbrun J, Baker D (Mar 2006) Multipass membrane protein structure prediction using Rosetta., Proteins, 62 (4), 1010-25
  • Yu FH, Yarov-Yarovoy V, Gutman GA, Catterall WA (Dec 2005) Overview of molecular relationships in the voltage-gated ion channel superfamily., Pharmacological reviews, 57 (4), 387-95
  • Zhao Y, Yarov-Yarovoy V, Scheuer T, Catterall WA (Mar 2004) A gating hinge in Na+ channels; a molecular switch for electrical signaling., Neuron, 41 (6), 859-65
  • Liu G, Yarov-Yarovoy V, Nobbs M, Clare JJ, Scheuer T, Catterall WA (Mar 2003) Differential interactions of lamotrigine and related drugs with transmembrane segment IVS6 of voltage-gated sodium channels., Neuropharmacology, 44 (3), 413-22
  • Yarov-Yarovoy V, McPhee JC, Idsvoog D, Pate C, Scheuer T, Catterall WA (Sep 2002) Role of amino acid residues in transmembrane segments IS6 and IIS6 of the Na+ channel alpha subunit in voltage-dependent gating and drug block., The Journal of biological chemistry, 277 (38), 35393-401
  • Yarov-Yarovoy V, Brown J, Sharp EM, Clare JJ, Scheuer T, Catterall WA (2001) Molecular determinants of voltage-dependent gating and binding of pore-blocking drugs in transmembrane segment IIIS6 of the Na(+) channel alpha subunit, Journal of Biological Chemistry, 276(1), 20-7.
  • Garlid KD, Paucek P, Yarov-Yarovoy V, Murray HN, Darbenzio RB, D'Alonzo AJ, Lodge NJ, Smith MA, Grover GJ (2007) Cardioprotective effect of diazoxide and its interaction with mitochondrial ATP-sensitive K+ channels. Possible mechanism of cardioprotection, Circulation Research, 81(6), 1072-82.