Thin filament dysfunctions caused by mutations in tropomyosin Tpm3.12 and Tpm1.1

Joanna Moraczewska

doi:10.1007/s10974-019-09532-y

Abstract

Tropomyosin is the major regulator of the thin filament. In striated muscle its function is to bind troponin complex and control the access of myosin heads to actin in a Ca2+-dependent manner. It also participates in the maintenance of thin filament length by regulation of tropomodulin and leiomodin, the pointed end-binding proteins. Because the size of the overlap between actin and myosin filaments affects the number of myosin heads which interact with actin, the filament length is one of the determinants of force development. Numerous point mutations in genes encoding tropomyosin lead to single amino acid substitutions along the entire length of the coiled coil that are associated with various types of cardiomyopathy and skeletal muscle disease. Specific regions of tropomyosin interact with different binding partners; therefore, the mutations affect diverse tropomyosin functions. In this review, results of studies on mutations in the genes TPM1 and TPM3, encoding Tpm1.1 and Tpm3.12, are described. The paper is particularly focused on mutation-dependent alterations in the mechanisms of actin-myosin interactions and dynamics of the thin filament at the pointed end.

Highlights

The thin filaments of striated muscle contain actin polymers coated with tropomyosin (Tpm) and regularly spaced troponin (Tn)
Tropomyosin extends along the entire length of the thin filament where it interacts with Tmod or Lmod and is involved in the maintenance of the correct length of the thin filament (Gregorio et al 1995; Tsukada et al 2010)
Different phenotypes observed in Tpm1.1-dependent cardiomyopathy or Tpm3.12-dependent skeletal muscle myopathy strongly suggest that the mutations must cause structural distortions in regions of the tropomyosin molecule, which differentially affect the functions of the thin filament

Summary

Introduction

The thin filaments of striated muscle contain actin polymers coated with tropomyosin (Tpm) and regularly spaced troponin (Tn). Predominance and hypotrophy of slow, type 1 muscle fibers in the absence of other pathological features such as nemaline bodies is dominant in CFTD, though distortion of the Z-disc can occur Both conditions present hypocontractile phenotype with various levels of muscle weakness, which correlates with reduced acto-myosin ATPase activation and lower force production in isolated muscle fibers (Clarke 2008; Kee and Hardeman 2008). Different phenotypes observed in Tpm1.1-dependent cardiomyopathy or Tpm3.12-dependent skeletal muscle myopathy strongly suggest that the mutations must cause structural distortions in regions of the tropomyosin molecule, which differentially affect the functions of the thin filament. Because tropomyosin self-polymerizes, and binds F-actin, troponin, Tmod and Lmod (Fig. 1c), localization of the mutation-linked substitutions along the molecule potentially can affect any of these different interactions

Interactions of tropomyosin with actin

Binding of troponin to the thin filament

The thin filament activation states

Regulation of interactions at the pointed end of the thin filament