Author: Michael Greenberg

Skeletal muscle actin mutations are well known to cause skeletal myopathies, but their role in cardiomyopathies has been controversial as skeletal muscle actin is only expressed at modest levels in the heart. Here, we demonstrate that a skeletal muscle actin mutation potently causes multiple defects in actin function at the atomic and molecular scales, and it functions in a dominant fashion, leading to cardiomyocyte contractile defects. Our results establish how skeletal muscle actin mutations may cause cardiomyocyte dysfunction and lay the foundation for future studies of the role of skeletal muscle actin in cardiomyopathy. The article can be found here.

This was a fun collaboration, lead by the Morley lab.  Congratulations to all of the authors! The paper can be found here.

Congratulations to first author, Dr. Brent Scott, and our collaborators at the University of Kentucky, Drs. Caterina Squari and Ken Campbell.  We show that although danicamtiv was originally described as a myosin activator, its molecular mechanism is more complicated, where it likely activates the sarcomere through the thin filament.  The paper can be found here.

Congratulations to Brent Scott for winning the BMB Postdoctoral Research Discovery and Innovation Award.

Together, we used single molecule techniques, in vitro reconstitution assays, and molecular dynamics simulations to demonstrate that this linker region is intrinsically disordered and dynamic in the context of isolated troponin and the fully-regulated thin filament.  We also demonstrate how rigorous tools developed by the intrinsically disordered protein field can provide new insights into the structural mechanisms underlying human cardiomyopathy mutations. Congratulations to all of our co-authors! The paper can be found here.

Welcome to Ella Mozier, a new graduate student in the lab who will be co-mentored with Andrea Soranno.

Familial dilated cardiomyopathy (DCM) is frequently caused by autosomal dominant point mutations in genes involved in diverse cellular processes, including sarcomeric contraction. While patient studies have defined the genetic landscape of DCM, genetics are not currently used in patient care, and patients receive similar treatments regardless of the underlying mutation. It has been suggested that a precision medicine approach based on the molecular mechanism of the underlying mutation could improve outcomes; however, realizing this approach has been challenging due to difficulties linking genotype and phenotype and then leveraging this information to identify therapeutic approaches. Here, we used multiscale experimental and computational approaches to test whether knowledge of molecular mechanism could be harnessed to connect genotype, phenotype, and drug response for a DCM mutation in troponin T, deletion of K210. Previously,…

Skeletal muscle actin mutations are well-known to cause skeletal myopathies, but their role in cardiomyopathies have been controversial as skeletal muscle actin is only expressed at modest levels in the heart.  Here, we demonstrate that a skeletal muscle actin mutation potently causes multiple defects in actin function at the atomic and molecular scales, and it functions in a dominant fashion, leading to cardiomyocyte contractile defects.  Our results establish how skeletal muscle actin mutations may cause cardiomyocyte dysfunction and lay the foundation for future studies of the role of skeletal muscle actin in cardiomyopathy.  The paper can be found here. Congratulations to all of the authors, including our collaborators: Drs. Silvia Jansen, Rui Zhang, and Kory Lavine.

The preprint can be found here.  Thank you to Gretchen Meyer and our other collaborators for including us.

Congratulations to all of the authors.  The publication can be found here.