Access Type
Open Access Dissertation
Date of Award
January 2018
Degree Type
Dissertation
Degree Name
Ph.D.
Department
Chemistry
First Advisor
Young-Hoon Ahn
Abstract
Reactive oxygen species (ROS) are important signaling molecules that contribute to the etiology of multiple muscle-related diseases, including cardiomyopathy and heart failure. There is emerging evidence that cellular stress can lead to destabilization of sarcomeres, the contractile unit of muscle. However, it is not completely understood how cellular stress or ROS induce structural destabilization of sarcomeres or myofibrils. Protein glutathionylation is one of the major protein cysteine oxidative modifications that play an important role in redox signaling and oxidative stress. In this report, we used a clickable glutathione approach in a cardiomyocyte cell line, and found that SET and MYND Domain Containing 2 (SMYD2), lysine methyltransferase, can be selectively glutathionylated at Cys13. Functional studies showed that SMYD2 Cys13 glutathionylation serve as a key molecular event that leads to a loss of myofibril integrity and degradation of sarcomeric proteins mediated by matrix metalloprotease 2 (MMP-2) and calpain 1. Biochemical analysis demonstrated that SMYD2 glutathionylated at Cys13 loses its interaction with Hsp90 and N2A, a domain of titin that is important for stress-sensing. Upon dissociation from SMYD2, N2A or titin was susceptible to degradation by MMP-2, suggesting a protective role of SMYD2 in sarcomere stability. Taken together, our results identify SMYD2 glutathionylation as a novel molecular mechanism by which ROS contribute to sarcomere destabilization and potentially muscle dysfunction.
Recommended Citation
Munkanatta Godage, Dhanushka Nalin Perera, "Functional Study Of Smyd2 Glutathionylation In Cardiomyocytes" (2018). Wayne State University Dissertations. 2051.
https://digitalcommons.wayne.edu/oa_dissertations/2051