Voula Kanelis

faculty_img Academic Title: Associate Professor

Campus: UTM

CSB Appointment: Cross Appointment

Primary Undergraduate Department:
Chemistry, UTM

Graduate Programs:
Cell & Systems Biology

Titles and Honors:
CIHR New Investigator (2012)

Academic or Administrative Appointments:
Education:
Ph.D. University of Toronto 2001
B.Sc. University of Western Ontario 1995

 

Mailing Address
Department of Cell & Systems Biology
University of Toronto
3359 Mississauga Road North
Mississauga, ON L5L 1C6
Canada

 

Contact Information
Office phone: 905-569-4542
Office: DV 4042
Lab:
Lab phone:
Email: voula.kanelis@utoronto.ca
URL: sites.google.com/site/kanelislaboratory/

 

Research Areas
Structural Biology

 

Research

Research in the laboratory is focused primarily on the sulfonylurea receptor (SUR) protein family. SUR proteins are members of the ATP-binding cassette (ABC) superfamily of transporters, which are integral membrane proteins found in all species. Unlike most ABC proteins, the SUR proteins do not possess any transporter activity, but form the regulatory subunits in ATP-sensitive potassium (K-ATP) channels. Four copies of the SUR proteins surround four copies of the pore-forming Kir6.x (Kir6.1 or Kir6.2) proteins to form K-ATP channels. Different combinations of SUR and Kir6.x proteins combine to form K-ATP channels in various tissues. ATP binding at the Kir6.x proteins results in K-ATP channel inhibition whereas MgATP binding and hydrolysis at the SUR NBDs results in channel opening. NBD1 and NBD2 of SUR2A are also sites of phosphorylation by protein kinase A, which results in results in KATP channel activation. SUR-mediated regulation of KATP channels is critical for cardiovascular and pancreatic function. Over 150 different mutations that cause diseases related to insulin production have been identified in the various regions of SUR1, including in the NBDs. Mutations in the NBDs of SUR2A cause dilated cardiomyopathy, atrial fibrillation, and increased risk of myocardial infarction. Therefore, studies of the SUR NBDs are critical to understanding the mechanism of K-ATP channel regulation and its dysfunction in diseases. We have adopted an interdisciplinary approach to studies of the SUR NBDs. We use a variety of biophysical tools (NMR spectroscopy, CD spectroscopy, fluorescence spectroscopy), biochemical methods (limited proteolysis, nucleotide binding and hydrolysis assays), and bioinformatics analysis of NBD and ABC structure in the research. Our research has already provided insights into the structural domain boundaries and regulatory regions of NBD1 from SUR2A and SUR1 (De Araujo … Kanelis, 2011). We have also examined the effects of the disease-causing mutation V730I (De Araujo, Lopez-Alonso, Kanelis, manuscript in preparation) and phosphorylation (De Araujo, Alvarez, Kanelis, manuscript in preparation) on the structure and dynamics of SUR2A. Further, we have demonstrated that SUR2A NBD1 is a site of interaction of the KATP channel opener (KCO) drug pinacidil, and that drug-binding increases the affinity of SUR2A NBD1 for nucleotide (López-Alonso, De Araujo, Kanelis, 2013), which has important implications for the mechanism of action of this widely studied drug. Currently, we are studying the interaction of SUR2A NBD1 with novel compounds. We are also studying the interaction of SUR2A NBD1 with different regions of SUR2A, and are extending these studies to SUR1. Further, we are currently running experiments to assign the NMR spectra of SUR2A NBD1 so that our interaction, mutation, and phosphorylation studies may be analyzed at the level of individual residues.

 

Publications

2014

Top
Successful development and use of a thermodynamic stability screen for optimizing the yield of nucleotide binding domains.de Araujo ED, Kanelis V.Protein Expr. Purif. 2014 Nov;103:38-47
pubmed
HNH proteins are a widespread component of phage DNA packaging machines.Kala S, Cumby N, Sadowski PD, Hyder BZ, Kanelis V, Davidson AR, Maxwell KL.Proc. Natl. Acad. Sci. U.S.A. 2014 Apr;111(16):6022-7
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2012

Top
NMR and fluorescence studies of drug binding to the first nucleotide binding domain of SUR2A.López-Alonso JP, de Araujo ED, Kanelis V.Biochemistry 2012 Nov;51(45):9211-22
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The protein gp74 from the bacteriophage HK97 functions as a HNH endonuclease.Moodley S, Maxwell KL, Kanelis V.Protein Sci. 2012 Jun;21(6):809-18
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2011

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The first nucleotide binding domain of the sulfonylurea receptor 2A contains regulatory elements and is folded and functions as an independent module.de Araujo ED, Ikeda LK, Tzvetkova S, Kanelis V.Biochemistry 2011 Aug;50(31):6655-66
pubmed
NMR spectroscopy to study the dynamics and interactions of CFTR.Kanelis V, Chong PA, Forman-Kay JD.Methods Mol. Biol. 2011;741:377-403
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2010

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The solution structure of the C-terminal Ig-like domain of the bacteriophage λ tail tube protein.Pell LG, Gasmi-Seabrook GM, Morais M, Neudecker P, Kanelis V, Bona D, Donaldson LW, Edwards AM, Howell PL, Davidson AR, Maxwell KL.J. Mol. Biol. 2010 Oct;403(3):468-79
pubmed
NMR evidence for differential phosphorylation-dependent interactions in WT and DeltaF508 CFTR.Kanelis V, Hudson RP, Thibodeau PH, Thomas PJ, Forman-Kay JD.EMBO J. 2010 Jan;29(1):263-77
pubmed

2009

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The phage lambda major tail protein structure reveals a common evolution for long-tailed phages and the type VI bacterial secretion system.Pell LG, Kanelis V, Donaldson LW, Howell PL, Davidson AR.Proc. Natl. Acad. Sci. U.S.A. 2009 Mar;106(11):4160-5
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2008

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Regulation of Nedd4-2 self-ubiquitination and stability by a PY motif located within its HECT-domain.Bruce MC, Kanelis V, Fouladkou F, Debonneville A, Staub O, Rotin D.Biochem. J. 2008 Oct;415(1):155-63
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2007

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CFTR regulatory region interacts with NBD1 predominantly via multiple transient helices.Baker JM, Hudson RP, Kanelis V, Choy WY, Thibodeau PH, Thomas PJ, Forman-Kay JD.Nat. Struct. Mol. Biol. 2007 Aug;14(8):738-45
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Nuclear magnetic resonance (NMR) solution structure, dynamics, and binding properties of the kringle IV type 8 module of apolipoprotein(a).Chitayat S, Kanelis V, Koschinsky ML, Smith SP.Biochemistry 2007 Feb;46(7):1732-42
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2006

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Isotope labeling strategies for the study of high-molecular-weight proteins by solution NMR spectroscopy.Tugarinov V, Kanelis V, Kay LE.Nat Protoc 2006;1(2):749-54
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Structural determinants for high-affinity binding in a Nedd4 WW3* domain-Comm PY motif complex.Kanelis V, Bruce MC, Skrynnikov NR, Rotin D, Forman-Kay JD.Structure 2006 Mar;14(3):543-53
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2004

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Probing slow dynamics in high molecular weight proteins by methyl-TROSY NMR spectroscopy: application to a 723-residue enzyme.Korzhnev DM, Kloiber K, Kanelis V, Tugarinov V, Kay LE.J. Am. Chem. Soc. 2004 Mar;126(12):3964-73
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2003

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Affinity and specificity of interactions between Nedd4 isoforms and the epithelial Na+ channel.Henry PC, Kanelis V, O'Brien MC, Kim B, Gautschi I, Forman-Kay J, Schild L, Rotin D.J. Biol. Chem. 2003 May;278(22):20019-28
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