Obscure functions: the location-function relationship of obscurins

Abstract

The obscurin family of polypeptides is essential for normal striated muscle function and contributes to the pathogenesis of fatal diseases, including cardiomyopathies and cancers. The single mammalian obscurin gene, OBSCN, gives rise to giant (∼800 kDa) and smaller (∼40-500 kDa) proteins that are composed of tandem adhesion and signaling motifs. Mammalian obscurin proteins are expressed in a variety of cell types, including striated muscles, and localize to distinct subcellular compartments where they contribute to diverse cellular processes. Obscurin homologs in Caenorhabditis elegans and Drosophila possess a similar domain architecture and are also expressed in striated muscles. The long sought after question, "what does obscurin do?" is complex and cannot be addressed without taking into consideration the subcellular distribution of these proteins and local isoform concentration. Herein, we present an overview of the functions of obscurins and begin to define the intricate relationship between their subcellular distributions and functions in striated muscles.

Keywords: Cardiac muscle; Cardiomyopathy; Molecular scaffold; Skeletal muscle; UNC-89.

Fig. 1

Alternative splicing of the tandem adhesion and signaling motifs encoded by the obscurin gene (OBSCN) creates diverse obscurin proteins. The domain architecture for known human, mouse, and Caenorhabditis elegans isoforms are shown. Predicted domain architecture for Drosophila obscurin isoforms are also shown. Obscurin isoforms are divided into non-kinase isoforms (a) and kinase-containing isoforms (b). See key for domain architecture. Pink box within the NH₂-terminus of UNC-89-D and obscurin-E (Drosophila) indicates unique amino acids specific to each isoform and species. FnIII Fibronectin type-III, Ig immunoglobulin, MLCK myosin light-chain kinase, N-, -C NH₂- and COOH-terminus, respectively, PH pleckstrin homology, RhoGEF rho-guanine nucleotide exchange factor, SH3 src homology-3

Fig. 2

Subcellular distribution of mammalian obscurin proteins in skeletal and cardiac muscle. Known locations for obscurins are highlighted by a distinct color: purple subsarcolemma, light green nulei, blue intercalated disc, yellow neuromuscular junction, orange A/I junction, dark green Z-disc, red M-band. A summary of the functions of obscurin at these locations is also noted. PP2A Protein phosphatase 2, RhoA Ras homolog gene family, member A, SR sarcoplasmic reticulum

Fig. 3

Epitope mapping of published antibodies of mammalian obscurins. For simplicity, antibodies specific for C. elegans and Drosophila obscurins are not included. See Table 1 for complete description of antibodies, subcellular distributions and references and Fig. 1 for definitions of domains

Fig. 4

A cartoon depiction of the variants of the obscurin gene (OBSCN) and where they map to on the obscurin protein. Dilated and hypertrophic cardiomyopathies and left ventricular non-compaction are highlighted in green, red, and blue, respectively. fs Frameshift mutations