Biochemistry

Howard Young

Howard Young

Ph.D, University of Connecticut
Molecular Biology and Biochemistry


Professor

Office: 780-492-3931
Lab: 780-492-4577
Fax: 780-492-0886
hyoung@ualberta.ca

Research:

Inside heart cells, changes in calcium metabolism control the rate and force of muscle contraction and relaxation. With each heart beat, calcium is released from a storage compartment (the ‘sarcoplasmic reticulum’) for muscle contraction and pumped back into the storage compartment for muscle relaxation. Defects in this process are known to be associated with heart failure, and hereditary forms of heart disease may be more common than originally thought. Recently, families suffering from inherited heart disease have been found to have defects at a particular step in calcium metabolism (in proteins called ‘phospholamban’ and ‘sarcolipin’). These defects interfere with the ability of the heart to respond to changes in calcium metabolism, yet we do not fully understand the reason the genetic defects cause heart failure. The premise of our research is that the development of treatments for heart disease requires detailed knowledge of the underlying disease-associated mechanisms. Given the link between phospholamban, sarcolipin and heart failure, a detailed understanding should lead to clinical improvement in patients suffering from heart disease. Our research focuses on detecting new mutations in heart failure patients and understanding the associated molecular defects in calcium metabolism. We focus on phospholamban, sarcolipin and the calcium pump, and how they work together to trigger muscle relaxation. We take the following approaches. We are sequencing the phospholamban and sarcolipin genes in ~1000 University of Alberta heart failure patients. New disease-associated mutations that we identify will be studied using biochemical and structural biology methods. The goal is to develop a detailed molecular understanding of how mutations lead to heart disease. If we can fully understand these details, we may be able to better diagnose and treat patients presenting with heart disease.

 

Selected Publications:

Regulation of the sarcoplasmic reticulum calcium pump by divergent phospholamban isoforms in zebrafish.
Gorski PA, Trieber CA, Ashrafi G, Young HS.
Journal of Biological Chemistry (2015) 290:6777-88.

Deception in simplicity: Hereditary phospholamban mutations in dilated cardiomyopathy.
Young HS, Ceholski DK, Trieber CA.
Biochemistry and Cell Biology (2015) 93:1-7.

Phospholamban C-terminal residues are critical determinants of the structure and function of the calcium ATPase regulatory complex.
Abrol N, Smolin N, Armanious G, Ceholski DK, Trieber CA, Young HS, Robia SL.
Journal of Biological Chemistry (2014) 289:25855-66.

Decreased capacity of sodium import into Arabidopsis chloroplasts impairs salt tolerance, photosynthesis and plant performance.
Müller M, Kunz HH, Schroeder JI, Kemp G, Young HS, Neuhaus HE.
The Plant Journal (2014) 78:646-58.

Membrane Transport Piece by Piece: Production of Transmembrane Peptides for Structural and Functional Studies.
Kemp G, Fliegel L, Young HS.
Current Protocols in Protein Science Supplement (2014) 75, Unit 29.8.

Sarco/endoplasmic reticulum calcium ATPase (SERCA) inhibition by sarcolipin is encoded in its luminal tail.
Gorski PA, Glaves JP, Vangheluwe P, Young HS.
J Biol Chem. (2013) Mar 22;288(12):8456-67.

Structure-function relation in phospholamban: Modulation of channel activity as a potential regulator of SERCA activity.
Smeazzetto S, Saponaro A, Young HS, Moncelli MR, Thiel G.
PLoS One. (2013) 8(1):e52744.

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.
Cortez LM, Kumar J, Renault L, Young HS, Sim VL.
J Biol Chem. (2013) Feb 15;288(7):4772-81.

Distinct morphological and electrophysiological properties of an elk prion peptide.
Glaves JP, Gorski PA, Alier K, Ma L, Renault L, Primeau JO, Jhamandas JH, Young HS.
Peptides (2013) 40C:49-56.

Hydrophobic imbalance in the cytoplasmic domain of phospholamban is a determinant for lethal dilated cardiomyopathy.
Ceholski DK, Trieber CA, Young HS.
Journal of Biological Chemistry (2012) 287:16521-9.

Lethal, hereditary mutants of phospholamban elude phosphorylation by protein kinase A.
Ceholski DK, Trieber CA, Holmes CF, Young HS.
Journal of Biological Chemistry (2012) 287:26596-605.

Transmembrane helix 11 is a genuine regulator of the endoplasmic reticulum Ca2+ pump and acts as a functional parallel of β-subunit on α-Na+,K+-ATPase.
Gorski PA, Trieber CA, Larivière E, Schuermans M, Wuytack F, Young HS, Vangheluwe P.
J Biol Chem. (2012) Jun 8;287(24):19876-85.

Role of pri-miRNA structure in miR-17~92 biogenesis.
Chaulk S, Thede GL, Kent OA, Xu Z, Gesner E, Veldhoen RA, Khanna SK, Goping IS, MacMillan AM, Mendell JT, Young HS, Fahlman RP, Glover JNM.
RNA Biology (2011) 8:1105-14.

Phosphorylation and mutation of phospholamban alter physical interactions with the sarcoplasmic reticulum calcium pump.
Glaves JP, Trieber CA, Ceholski, DK, Stokes DL, Young HS.
Journal of Molecular Biology (2011) 405:707-23.

Structure of the atrial natriuretic peptide receptor extracellular domain in the hormone bound and unbound states by single particle electron microscopy.
Ogawa H, Qiu Y, Huang L, Sam-Chang SW, Young HS, Misono K.
FEBS Journal (2009) 276:1347-55.