Titin–N2A: More than a signaling node?

Titin is the largest mammalian protein known to date (3–4 MD) and spans the entire length of the half-sarcomere from Z-disc to M-band (Labeit and Kolmerer, 1995b). As in the Z-disc, where titin filaments from opposite sarcomeres overlap, titin filaments from opposite half-sarcomeres are thought to overlap within the M-band, where they are interconnected by M-band proteins. Thus, titin filaments with opposite polarity overlap in both the Z-disc and M-band, forming a contiguous filament along the myofibril. This layout of titin within the muscle’s sarcomere makes it ideally suited to sense changes in mechanical loading. Indeed, mechanosensing by titin involves titin-binding proteins, of which several are intimately involved in atrophy/hypertrophy signaling. These titin-binding proteins are not randomly distributed along the titin molecule but are restricted to “hot spots”: one near the Z-disc, one in the M-band region, and another in the central and elastic I-band region (van der Pijl et al., 2019). One of these I-band hotspots localizes to the N2A element. The N2A element contains four Ig domains (I80–83) and several unique sequences, of which the 104-residue unique sequence (UN2A) with flanking Ig domains I80 and I81 is a major component (Labeit and Kolmerer, 1995b). Several proteins interact with the N2A element, such as SMYD2, P94/calpain3, and the muscle ankyrin repeat proteins (MARPs). Titin–N2A might also interact with the actin-based thin filament, presumably in a Ca2+-dependent manner (Dutta et al., 2018). This locking of the titin–N2A element to the thin filament might have significant mechanical effects by preventing the proximal tandem Ig segment from extending as sarcomeres are stretched, thereby forcing the PEVK segment to increase its extension, and therefore generate higher passive force. However, to date, strong evidence for this locking mechanism has been lacking.

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