CHE 598 Seminar: Redefining Leiomodin-2’s Role In Muscle Function: Insights Into Novel Binding Sites
About the event
SPEAKER: Madison Little, Ph.D. Candidate, WSU Voiland School of Chemical Engineering and Bioengineering
BIOGRAPHY:
Madison is a fourth year Bioengineering PhD candidate in the Voiland School of Chemical Engineering and Bioengineering at WSU. She obtained a BS degree in Biomedical Science from Northern Arizona University in 2021 and began her PhD at WSU shortly after. She works in the lab of Dr. Alla Kostyukova studying actin-binding proteins in cardiac muscle cells.
ABSTRACT:
Every heartbeat depends on the proper functioning of the sarcomere, the smallest contractile unit of striated muscle tissue. Striated muscle contraction is the result of interaction between thick myosin-based filaments and thin actin-based filaments of the sarcomere and is known to be driven by Ca2+. The length of the thin filament (TF) is crucial for heart function and is regulated at the pointed-end by the tropomodulin family of proteins; tropomodulin-1 (Tmod1) caps the end of the TF, and leiomodin-2 (Lmod2) acts as a “leaky cap” and allows elongation of the filament. Unlike Tmod1, Lmod2 can bind both the pointed-end and along the side of the TF. The domain organization of Lmod2 is similar to that of Tmod1, except for the addition of a C-terminal extension of ~20 kDa. Aside from a well-known actin-binding motif, a WH2 domain, little is known about the C-terminal extension. Mutations in the C-terminal extension of Lmod2 cause cardiac dysfunction in humans, highlighting the importance of this region in Lmod2 function. Recently, we demonstrated that Lmod2’s C-terminal extension contains 2 additional actin-binding regions that are required for binding the side of the TF, and that binding of Lmod2 to the TF is Ca2+-dependent. Location of binding of these novel actin-binding regions on the thin filament suggest that Lmod2 functions not only as a regulator of thin filament length, but also in regulating muscle contraction. While we know the general location of these 2 new binding regions, the specific residues that interact with actin are not yet known. Our ongoing studies focus on localization of these novel binding regions and identifying the amino acid residues involved in binding to the side of the TF so mutations in these residues can be studied in live cells to better understand sarcomere mechanics and human disease.