Group:MUZIC:Obscurin

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Obscurin

Introduction

Obscurin is a giant protein expressed in striated muscle cells. It`s one of the three giant scaffold proteins of the striated muscles (the others are titin and nebulin [1] the encoding gene is localized on chromosome 1 (1q42) and the protein product is about 800 kDa with multiple splice variants of different sizes. The protein architecture resembles the modular organization of titin and is composed of multiple Ig-like domains and Fibronectin-like domains arranged in tandem, with most of them encoded on single exons [2]. The obscurin gene (OBSCN) encodes for at least two splice variants, obscurin A and obscurin B[3] the common part of the two variants is composed of up to 67 Ig-like and fibronectin type III domains (Fn3). The COOH-terminal of the protein contains a calmodulin-binding IQ motif, an SH3 domain and a Rho guanine nucleotide exchange factor (GEF) domain followed by a non-modular sequence with multiple phosphorylation sites at the COOH-terminus. In the obscurin B variant, the skipping of exons 90 and 91 links the Ob67 domain to kinase exons leading to the formation of longer variants with two additional Ser/Thr kinase domains which can also be expressed separately from an internal promoter [4] [5]. As scaffold protein of the sarcomere obscurin has several binding partners, mechanical and signaling functions. Obscurin seems to be involved in the correct organization of myofibrils localized in different regions of the sarcomere at different stages of myofibrillogenesis, starting with the subsarcolemmal sarcomeres in early developing hearts [6]. In developing muscles, obscurin is predominantly found at the Z-disk. Later in development, several lines of evidence showed the predominant localization of the protein in the M-band of mature striated muscles. Both localizations seem predominantly determined by the interaction with titin [7]. The presence of the GEF domain at the COOH-terminus suggests a role as a linker between sarcomeric proteins and the G-protein regulated pathways in myofibrils. Moreover, an involvement of obscurin in the lateral alignment of myofibrils and the M-band associated Sarcoplasmic Reticulum (SR) has been suggested [8] due to the highly stable complex formed by the N-terminal domains of obscurin, the C-terminal M10 domain of titin and a linker region of myomesin, which drives the correct alignment of the M-band and SR [9] [10]. Immunofluorescence analysis demonstrated a peripheral localization with respect to the myofibrillar proteins, and therefore a transverse orientation of obscurin with respect to the filament axis, which can then form a link between the myofibril and the SR lipid membranes [11] [12].

Sequence annotation

The aminoacid sequences of human obscurin are deposited in the UniProt database (see Uniprot for [1]) and GenBank GenBank (OBSCN obscurin). The sequence provided in Figure 1 is based on the analysis of the human splice variants [13]. Based on these different splice pathways, at least 4 isoforms are predicted: 2 long isoforms, two shorter isoforms in the extremely C-terminal part are possible but currently uncharacterized.


Crystal Structure of the titin Ig-like domain Complex between the titin M10 (blue) - Obscurin like 1 (Red) (PDB entry: 2wp3 )

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)

Nikos Pinotsis, Andrea Ghisleni

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