Howard Young (PhD, University of Connecticut)
Department of Biochemistry
Faculty of Medicine & Dentistry
University of Alberta
327 Medical Sciences Building
Edmonton, Alberta, Canada T6G 2H7
Lab Tel: 780.492.4577
Our laboratory focuses on structure-function relationships in the regulation of calcium transport in the heart. We study the molecular structure of the Ca2+-ATPases from the endoplasmic reticulum (ER) and sarcoplasmic reticulum (SR) with the overall aim of revealing the molecular basis of calcium transport and mechanisms of regulation. These Ca2+-ATPases pump calcium from the cytosol at the expense of ATP, thereby lowering cellular calcium concentrations and triggering a variety of physiological responses including heart muscle relaxation. Defects in these calcium transport mechanisms have been implicated in heart disease (hypertrophy, cardiomyopathy, hypertension, end-stage heart failure).
To achieve these goals, we utilize electron cryomicroscopy, x-ray crystallography and biochemical techniques to study the structure and function of Ca2+-ATPases. The primary focus of our laboratory is the molecular basis for the regulation of heart muscle relaxation by phospholamban and sarcolipin. For these studies, we use a combination of biochemistry and electron and x-ray crystallography to obtain three-dimensional structural information. Two examples of our recent studies include (1) Electron crystallographic analyses examining the interaction between Ca2+-ATPase, phospholamban and sarcolipin in two-dimensional crystals; and (2) X-ray crystallographic analysis of the inhibitory complex of a mycotoxin bound to Ca2+-ATPase.
Gorski, P.A., Trieber, C.A., Ashrafi, G., Young, H.S. (2015) Regulation of the sarcoplasmic reticulum calcium pump by divergent phospholamban isoforms in zebrafish. Journal of Biological Chemistry 290:6777-88.
Young, H.S., Ceholski, D.K., Trieber, C.A. (2015) Deception in simplicity: Hereditary phospholamban mutations in dilated cardiomyopathy. Biochemistry and Cell Biology 93:1-7.
Abrol, N., Smolin, N., Armanious, G., Ceholski, D.K., Trieber, C.A., Young, H.S., Robia, S.L. Phospholamban C-terminal residues are critical determinants of the structure and function of the calcium ATPase regulatory complex. Journal of Biological Chemistry 289:25855-66.
Muller, M., Kunz, H.H., Schroeder, J., Kemp, G., Young, H.S., and Neuhaus, E. (2014) Decreased capacity of sodium import into Arabidopsis chloroplasts impairs salt tolerance, photosynthesis and plant performance. The Plant Journal (in press).
Kemp, G., Fliegel, L., and Young, H.S. (2014) Membrane Transport Piece by Piece: Production of Transmembrane Peptides for Structural and Functional Studies. Current Protocol in Protein Science Curr Protoc Protein Sci. 2014 Feb 3;75:Unit 29.8.
Ullah, A., Kemp, G., Lee, G., Alves, C., Young, H.S., Sykes, B.D., and Fliegel, L. (2013) Structural and functional analysis of transmembrane segment IV of the salt tolerance protein sod2. Journal of Biological Chemistry 288:24609-24624.
Gorski, P.A., Glaves, J.P., Vangheluwe, P., and Young, H.S. (2013) Sarco/endoplasmic reticulum calcium ATPase (SERCA) inhibition is encoded in its luminal tail. Journal of Biological Chemistry 288:8456-8467.
Smeazzetto, S., Saponaro, A., Young, H.S., Monicelli, M.R., and Thiel, G. (2013) Structure-function relation in phospholamban: Modulation of channel activity as a potential regulator of SERCA activity. PLoS One 8:(1):e52744.
Cortez, M., Kumar, J., Renault, L., Young, H.S., and Sim, V.L. (2013) Mouse prion protein polymorphism 108F/189V affects the kinetics of fibril formation and the response to seeding; evidence for a two-step nucleation polymerization mechanism. Journal of Biological Chemistry 288:4772-4781.
Glaves, J.P., Gorski, P.A., Alier, K., Ma, L., Primeau, J.O., Jhamandas, J.H., and Young, H.S. (2013) Distinct morphological and electrophysiological properties of an elk prion peptide. Peptides 40:49-56.
Ceholski, D.K., Trieber, C.A., and Young, H.S. (2012) Hydrophobic imbalance in the cytoplasmic domain of phospholamban is a determinant for lethal dilated cardiomyopathy. Journal of Biological Chemistry 287:16521-16529.
Ceholski, D.K., Trieber, C.A., Holmes, C.F., and Young, H.S. (2012) Lethal, hereditary mutants of phospholamban elude phosphorylation by protein kinase A. Journal of Biological Chemistry 287:26596-26605.
Gorski, P.A., Trieber, C.A., Lariviere, E., Schuermans, M., Wuytack, F., Young, H.S. and Vangheluwe, P. (2012) Transmembrane helix 11 is a genuine regulator of the endoplasmic reticulum Ca2+ pump and acts as a functional parallel of b-subunit on a-Na+, K+-ATPase. Journal of Biological Chemistry 287:19876-19885.
Chaulk, S., Thede, G.L., Kent, O.A., Xu, Z., Gesner, E., Veldhoen, R.A., Khanna, S.K., Goping, I.S., MacMillan, A.M., Mendell, J.T., Young, H.S., Fahlman, R.P., Glover, J.N.M. (2011) Role of pri-miRNA structure in miR-17~92 biogenesis. RNA Biology 8:1105-14.
Misono, K., Philo, J., Arakawa, T., Ogata, C., Qiu, Y., Ogawa, H., Young, H.S. (2011) Structure, signaling mechanism and regulation of natriuretic peptide receptor-guanylate cyclase. FEBS Journal 278:1818-29.3.
Glaves, J.P., Trieber, C.A., Ceholski, D.K., Stokes, D.L., Young, H.S. (2011) Phosphorylation and mutation of phospholamban alter physical interactions with the sarcoplasmic reticulum calcium pump. Journal of Molecular Biology 405:707-23.