Howard Young

 

Exciting news:

As part of SPP-ARC (Striving for Pandemic Preparedness, an Alberta Research Consortium), we are establishing a state-of-the-art cryogenic electron microscopy (cryo-EM) facility. We are acquiring a Titan Krios G4 and a Talos L120C. Opening in the Fall 2024!

 

Research:

Inside heart cells, changes in calcium metabolism control the rate and force of muscle contraction and relaxation. With each heartbeat, 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. Furthermore, a new activator of calcium metabolism, DWORF (dwarf open reading frame) has recently been discovered. The premise of our research is that the development of treatments for heart disease requires detailed knowledge of the underlying regulatory and disease-associated mechanisms. Given the link between phospholamban, sarcolipin, DWORF and heart failure, a detailed understanding will lead to clinical improvement in patients suffering from heart disease. Our research focuses on detecting new mutations in heart failure patients, understanding the associated molecular defects, and restoring normal calcium metabolism. We focus on phospholamban, sarcolipin, DWORF and the calcium pump, and how they work together to trigger muscle relaxation. We use a combination of biochemical and structure biology approaches including X-ray crystallography and cryogenic electron microscopy (cryo-EM). 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.

Tenure:

I have been a member of the Biochemistry department for 22 years.

 

Selected Publications:

Missense variants in phospholamban and cardiac myosin binding protein identified in patients with a family history and clinical diagnosis of dilated cardiomyopathy. Biochimica et Biophysica Acta
Armanious, G.P., Lemieux, M.J., Espinoza-Fonseca, L.M., Young HS.
Molecular Cell Research (2024) (online ahead of print).

Replacement of Lys27 by asparagine in the SERCA regulator myoregulin: A Ca2+ affinity modulator or a catalytic activity switch? Biochimica et Biophysica Acta 
Rathod, N., Guerrero-Serna, G., Young, H.S., Espinoza-Fonseca, L.M.   
Molecular Cell Research (2024)1871:11963

Functional role of an unusual transmembrane acidic residue in the calcium pump regulator myoregulin. 
Liu, A.Y., Rathod, N., Guerrero-Serna, G., Young, H.S., Espinoza-Fonseca, L.M.   
Biochemistry (2023) 62:1331-36

Primitive phospholamban- and sarcolipin-like peptides inhibit the sarcoplasmic reticulum calcium pump SERCA.
Bak, J.J., Aguayo-Ortiz, R., Rathod, N., Primeau, J.O., Khan, M.B., Robia, S.L., Lemieux, M.J., Espinoza-Fonseca, L.M., Young, H.S
Biochemistry (2022) 61:1419-30

Nothing regular about the regulins: Distinct functional properties of SERCA transmembrane peptide regulatory subunits. 
Rathod, N., Bak, J.J., Primeau, J.O., Fisher, M.E., Espinoza-Fonseca, L.M., Lemieux, M.J., Young, H.S.   
International Journal of Molecular Sciences (2021) 22:8891.

Stimulation of Ca2+-ATPase transport activity by a small-molecule drug. 
Sordi, G., Goti, A., Young, H.S., Palchetti, I., Tadini-Buoninsegni, F.  
Chem Med Chem (2021) (epub)

Dwarf open reading frame (DWORF) is a direct activator of the sarcoplasmic reticulum calcium pump SERCA. 
Fisher, M.E., Bovo, E., Aguayo-Ortiz, R. Cho, E.E., Pribadi, M.P., Dalton, M.P., Rathod, N., Lemieux, M.J., Espinoza-Fonseca, L.M., Robia, S.L., Zima, A.V., Young, H.S.  
eLife (2021) (doi: 10.7554/eLife.65545).

Helical membrane protein crystallization in the new era of electron cryo-microscopy. 
Hernando, M.D., Primeua, J.O., Young, H.S.  
Methods in Molecular Biology (2021) 2302:179-199.

Interaction of a sarcolipin monomer and pentamer with the sarcoplasmic reticulum calcium pump SERCA. 
Glaves, J.P., Primeau, J.O., Espinoza-Fonseca, L.M., Lemieux, M.J., Young, H.S.
Biophysical Journal (2020) 118:518-31.

The phospholamban pentamer interacts with the sarcoplasmic reticulum calcium pump SERCA.
Glaves, J.P.*, Primeau, J.O.*, Espinoza-Fonseca, L.M., Lemieux, M.J., Young HS.
Biophysical Journal (2019) 116:633-47.

 

Life outside the lab