Tropomodulins: Pointed‐end capping proteins that regulate actin filament architecture in diverse cell types

Abstract

Tropomodulins are a family of four proteins (Tmods 1–4) that cap the pointed ends of actin filaments in actin cytoskeletal structures in a developmentally regulated and tissue‐specific manner. Unique among capping proteins, Tmods also bind tropomyosins (TMs), which greatly enhance the actin filament pointed‐end capping activity of Tmods. Tmods are defined by a TM‐regulated/Pointed‐End Actin Capping (TM‐Cap) domain in their unstructured N‐terminal portion, followed by a compact, folded Leucine‐Rich Repeat/Pointed‐End Actin Capping (LRR‐Cap) domain. By inhibiting actin monomer association and dissociation from pointed ends, Tmods regulate actin dynamics and turnover, stabilizing actin filament lengths and cytoskeletal architecture. In this review, we summarize the genes, structural features, molecular and biochemical properties, actin regulatory mechanisms, expression patterns, and cell and tissue functions of Tmods. By understanding Tmods' functions in the context of their molecular structure, actin regulation, binding partners, and related variants (leiomodins 1–3), we can draw broad conclusions that can explain the diverse morphological and functional phenotypes that arise from Tmod perturbation experiments in vitro and in vivo. Tmod‐based stabilization and organization of intracellular actin filament networks provide key insights into how the emergent properties of the actin cytoskeleton drive tissue morphogenesis and physiology. © 2012 Wiley Periodicals, Inc

Mechanisms of leiomodin 2-mediated regulation of actin filament in muscle cells

“…The first ∼340 residues are about 45% identical to the pointed-end capping protein tropomodulin 1 (Tmod1) (21) and contain a tropomyosin-binding helix (TM-h) and two actin-binding sites [an actin-binding helix (A-h) and a leucine-rich repeat (LRR) domain] (Fig. 1A and Figs.…”

Comprehensive computational analysis of leucine-rich repeat (LRR) proteins encoded in the genome of the diatom Phaeodactylum tricornutum

“…Although many of the P. tricornutum RI like LRR domains display homology to intracellular mammalian or plant nucleotide binding LRR proteins, they obviously have a different functionality as they lack the effector binding and the nucleotide binding oligomerization domain (NOD) (Inohara et al, 2005). Conversely, the LRR only protein ID 47725 contains several irregular RI like LRR motifs which are related to LRRs found in tropomodulins, involved in regulation of the dynamics of the actin cytoskel eton (Yamashiro et al, 2012). However, tropomodulins contain only a five LRR motif stretch, while ID 47725 contains two longer LRR domains inter connected with an unstructured amino acid strand.…”

Tropomyosin is required for cardiac morphogenesis, myofibril assembly, and formation of adherens junctions in the developing mouse embryo

“…At the pointed ends of cardiac muscle thin filaments, the N-terminus of αTM1 interacts with Tmod1, an actin pointed-end capping protein that stabilizes F-actin and regulates F-actin lengths Littlefield et al, 2001;Mudry et al, 2003;Moyer et al, 2010;Gokhin and Fowler, 2011;Yamashiro et al, 2012). Tmod1 and αTM1 function synergistically, whereby αTM1 greatly enhances the ability of Tmod1 to cap actin filament pointed ends, while Tmod1 enhances the ability of αTM1 to stabilize F-actin and prevent pointed-end depolymerization (Weber et al, 1994;Weber et al, 1999;Mudry et al, 2003;Kostyukova and Hitchcock-DeGregori, 2004).…”