Tropomodulin

Tropomodulins (Tmods) are a family of actin capping proteins that block actin association and dissociation at the slow growing (pointed) ends of actin filaments. There are four canonical, ~40 kD Tmod isoforms (Tmods1-4) in vertebrates, with tissue-specific and developmentally regulated patterns of expression. Tmod1 is expressed predominantly in terminally differentiated, post-mitotic cells (such as erythrocytes, lens fiber cells, neurons, and striated muscle), Tmod2 is expressed exclusively in neuronal tissues, Tmod3 is expressed ubiquitously, and Tmod4 is expressed exclusively in skeletal muscle. In addition to capping actin pointed ends, all Tmods also bind to tropomyosins (TMs), which bind along the side of actin filaments and enhance pointed end capping by Tmod. Tmods recognize TM isoforms with affinities differing by up to 100-fold, providing for diverse regulation of actin filaments coated with different TMs. Tmods have a modular structure with an unstructured N-terminal domain and a compact, globular C-terminal domain comprised of leucine-rich repeats (LRR). The N-terminal domain binds TM and actin and has TM-regulated pointed end capping activity, while the C-terminal domain binds actin but not TM, and caps pointed ends independently of TM. Both Tmod1 and Tmod3 can also bind actin monomers and nucleate actin filament assembly, providing another point of actin dynamics regulation. One focus of our laboratory’s research is the structure and function of Tmod family proteins and how they interact mechanistically with TMs and actin.

 

Key questions of interest are:

 

•  What is the molecular and structural basis for Tmods binding to actin at the pointed end, and how do Tmods affect actin on- and off-rates from growing or shrinking filaments?

 

•  What is the molecular and structural basis for Tmods binding to TMs, and how do TMs regulate Tmod capping?

 

•  What are the molecular, structural, and mechanistic relationships between actin filament pointed end capping, monomer binding, and nucleation by Tmod1 and Tmod3?

 

•  Do different Tmods have unique TM binding and actin regulatory properties tailored to specific actin cytoskeletal structures and/or different cell types?

 

•  What cellular signaling pathways and interacting proteins regulate Tmods’ binding to TMs and actin capping activities?

 

•  How does pointed-end capping by Tmods influence the biochemical activities of other actin-binding proteins (ADF/cofilin, profilin, Arp2/3 complex, capping protein, formins)?