Susan M. E. Smith 

  Associate Professor and Foundation Fellow
  Department of Biology & Physics  
  Kennesaw State University

Adjunct Assistant Professor
  Department of Pathology & Laboratory Medicine
  Emory School of Medicine
  Office: Science Lab Bldg Rm 3004
  Lab: Science Center Bldg Rm 350

  Mailing Address:
  Department of Biology and Physics
  Kennesaw State University           

  1000 Chastain Road, Bldg. 12 Rm 308
  Kennesaw, GA 30144  USA                                                                            +1 470-578-2794
My research centers around the mechanisms that control the activities of proteins that participate in cell signaling.  I use evolutionary comparisons of protein sequences and molecular modeling to predict the parts of proteins most likely to control their activity.  And then I test those predictions in the laboratory, using a combination of techniques to perturb ksu logoand measure activity.  I investigate the structure, function and control of NADPH oxidases (Nox) and of voltage-gated proton channels (Hv1).  Noxes and Hv1 are known to work together in several cell types, and both produce signals important not only to human health but also to the development, physiology, and lifestyles of many other organisms. Currently I have three excellent undergraduate assistants and a MS student.
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Hv1 Structure, Function, and Control I use sequence analysis and molecular models to help inform mutagenesis, electrophysiology, and other experiments investigating the control of Hv1 activity, important to signaling in many cells and organisms.
Hv1 Molecular Model
Modeling of voltage sensor domains (VSD) is tricky because the mobility of the S4 helix allows different alignments of the 'arginine registry' depending on the functional state of the sensor.  I used phylogenetic analysis and a structurally informed alignment method to fix the registry to the open state, and then Kethika Kullepumera in Régis Pomès's lab tested two alternative homology models with massively repeated molecular dynamics simulations.  The preferred model from this analysis produced a hypothesis about the accessibility of the third arginine on S4, which when tested via patch clamp in
Tom DeCoursey's lab turns out to be accessible to the solution on the inside of the membrane, even in the open state.

Hv1 Selectivity Filter -- and it wanders!
My sequence and phylogenetic analysis, combined with my molecular model, provided a good template from which to make substitutio
ns aimed at affecting proton conduction.  The electrophysiology expertise of the DeCoursey lab enabled us to use these mutants to find (an essential part of) the selectivity filter of Hv1.  Surprisingly, most mutants at this site convert the perfectly proton selective Hv1 to an anion selective channel.  Also surprisingly, we can move the selectivity filter up one turn (but not down one turn) and retain the apparently perfect selectivity.  

Dinoflagellate Bioluminescence
I developed signature sequences to predict Hv1’s in other organisms.  With Al Place’s help, we found a putative Hv1 gene in a dinoflagellate cDNA library, now confirmed as a bona fide Hv1 protein by patch clamping in Tom DeCoursey's lab.  In this multidisciplinary project, we are exploring Woody Hastings’ proposal that Hv1 activity triggers the bioluminescent flash. 

Here's a link about our discovery of a dinoflagellate proton channel gene, with an illustration of how we think it works to trigger bioluminescence: story

This paper's results got picked up by several popular science sources -- I guess everyone likes bioluminescence!  This German one makes it 'world famous':!85585/


Recent Hv1-related Publications:

vsd phylogenetics
Jin, C., J. Sun, C.A. Stilphen, S.M.E. Smith, H. Ocasio, B. Bermingham, S. Darji, A. Guha, R. Patel, A.M. Geurts, H.J. Jacob, N.A. Lambert, P.M. O’Connor.  2014.  HV1 acts as a sodium sensor and promotes superoxide production in medullary thick ascending limb of Dahl salt-sensitive rats.  Hypertension. 64, 540-50.

Morgan, D., B. Musset. K. Kulleperuma, S.M.E. Smith, S. Rajan, V.V. Cherny, R. Pomès, and T.E. DeCoursey. 2013. Peregrination of the Selectivity Filter Delineates the Pore of the Human Voltage Gated Proton Channel hHV1. J. Gen. Physiol. 142(6), 625-640.

Kulleperuma, K., Smith, S.M.E., Morgan, D., Musset, B., Holyoake, J., Chakrabarti, N., Cherny, V.V., DeCoursey, T.E. & Pomès, R. (2013). Construction and validation of a homology model of the human voltage-gated proton channel hHV1. The Journal of General Physiology, 141(4), 445-465.

Musset, B., S.M.E. Smith, S. Rajan, D. Morgan, V.V. Cherny, and T.E. DeCoursey.  (2011).  Aspartate112 is the selectivity filter of the human voltage gated
proton channel.  Nature.  480: 273–277

Smith, S.M.E., D. Morgan, B. Musset, V.V. Cherny, A.R. Place, J.W. Hastings, and T.E. DeCoursey.  (2011).  A voltage-gated proton channel in a dinoflagellate.  Proceedings of the National Academy of Sciences, U.S.A. 2011 108:18162-18167

Musset, B., Smith SM, Rajan S, Cherny VV, Morgan D, DeCoursey TE. (2010). Oligomerization of the voltage gated proton channel. Channels. 4: 260-265. 
Musset, B., Smith SM, Rajan S, Cherny VV, Sujai S, Morgan D, DeCoursey TE. (2010). Zinc inhibition of monomeric and dimeric proton channels suggests cooperative gating. J Physiol. 588(Pt 9):1435-49

Nox Structure, Function, and Control

nox dh model I collaborate with Dave Lambeth's lab, using molecular models that I’ve built or helped to build to inform experiments, exploring different aspects of Nox structure and the isoform specific control of Nox activity, fundamental to understanding Nox's role as a signal generator.  I'm involved in a project to discover small molecule inhibitors of Noxes, which could eventually be useful in treating diseases; others on the project include James McCoy, Yerun Zhu, Yang Li, Becky Diebold and Aiming Sun.  We are also working with Shivaprakash Gangappa at the CDC, who is testing one of our compounds in a mouse model of influenza infection. 

Recent Nox-related Publications:
Diebold, B.A., S.M.E. Smith, Y. Li, J.D. Lambeth.  2014.  NOX2 as a target for Drug Development: Indications, Possible Complications and Progress.  Antioxidants and Redox Signaling. (Epub ahead of print, Mar 14 2014)

Lorincz, A.M., G. Szarvas, S.M.E. Smith, and E. Ligeti. 2013. Role of Rac GTPase activating proteins in regulation of NADPH oxidase in human neutrophils.  Free Rad. Biol. Med. 68, 65-71.

Smith, SME, J Min, T Ganesh, B Diebold, T Kawahara, Y Zhu, J McCoy, A Sun, JP Snyder, H Fu, Y Du, I Lewis, JD Lambeth.  2012. Ebselen and congeners inhibit NADPH-oxidase 2 (Nox2)-dependent superoxide generation by interrupting the binding of regulatory subunits.  Chem. Biol. 19, 752-763

        -- And a very nice write up in the same issue of Chemistry and Biology, pointing out the innovation in the HTS -- hats off to Tsukasa Kawahara for getting   this started!
             Bedard and Jaquet, 2012. Cell Free Screening for NOX Inhibitors. Chem. Biol. 19:

 Kawahara, T., Jackson, H.M., Smith, S.M.E., Simpson, P.D., Lambeth, J.D.  (2011).  Nox5 forms a functional oligomer mediated by self-association of its dehydrogenase domain.  Biochem. 50: 2013-25.

Jackson HM, Kawahara T, Nisimoto Y, Smith SM, Lambeth JD. (2010). Nox4 B-loop creates an interface between the transmembrane and dehydrogenase domains J Biol Chem. 285(14):10281-90

Other activities

Short courses – I have extensive experience teaching sequence analysis and molecular modeling to working professionals, in both short course and workshop format.  I can tailor a course or workshop to your lab’s or organization’s needs.  Contact me for details. 

Examples of Older Work
(Nitric Oxide Synthases; Polymerase-based methodology)

Jones RJ, Jourd'heuil D, Salerno JC, Smith SM, Singer HA. (2007). iNOS regulation by calcium/calmodulin-dependent protein kinase II in vascular smooth muscle.  Am J Physiol Heart Circ Physiol. 292:H2634-42.

Ghosh, D.K., M.A. Holliday, C. Thomas, J.B. Weinberg, S.M.E. Smith, and J.C. Salerno. (2006)  Nitric oxide synthase output state: design and properties of NOS oxygenase/FMN constructs.   J. Biol. Chem. 281: 14173-14178.

Jones, R.J., Y.T. Gao, T. Simone, J.C. Salerno, and S.M.E. Smith. (2006)  NADPH Analog binding to constitutive nitric oxide synthases activates electron transfer and NO synthesis. Nitric Oxide: Biology and Chemistry. 14: 228-237

Ingledew, W.J., S.M.E. Smith, Y.T. Gao, R.J. Jones, J.C. Salerno, and P.R. Rich.  (2005) Ligand, Co-Factor And Residue Vibrations In The Catalytic Site Of Endothelial Nitric Oxide Synthase. Biochemistry. 44(11):4238-46.

Erdogan, E., Jones, R.J., Hanna, M.H., Matzlin, P., Smith, S.M.E., and J.C. Salerno (2005) INSULT, a Novel Mutagenesis Method Generating High Yields Of Closed Circular Mutant DNA With One Primer Per Mutant. Molecular
Biotechnology, 30: 21-30.  

Salerno, J.C., Jones, R.J., Erdogan, E. and S.M.E. Smith (2005) A Single Stage Polymerase Based Procedure For The Introduction Of Deletions And Insertions Without Subcloning. Molecular Biotechnology, 29: 225-232.

Salerno, J.C., Harris, D., Irizarry, K., Morales, A., Smith, S.M.E., Roman, L., Martasek, P., Masters, B.S.S., Jones, C.L., Weissman, B.A., Liu, Q., and Gross, S.S. (1997) An Autoinhibitory Control Element Defines Calcium Regulated Isoforms Of NO Synthase  J. Biol. Chem. 272, 29769-29777
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