Conformation-regulated mechanosensory control via titin domains in cardiac muscle

Abstract

The giant filamentous protein titin is ideally positioned in the muscle sarcomere to sense mechanical stimuli and transform them into biochemical signals, such as those triggering cardiac hypertrophy. In this review, we ponder the evidence for signaling hotspots along the titin filament involved in mechanosensory control mechanisms. On the way, we distinguish between stress and strain as triggers of mechanical signaling events at the cardiac sarcomere. Whereas the Z-disk and M-band regions of titin may be prominently involved in sensing mechanical stress, signaling hotspots within the elastic I-band titin segment may respond primarily to mechanical strain. Common to both stress and strain sensor elements is their regulation by conformational changes in protein domains.

Fig. 1

Schematic of cardiac sarcomeres connected in series, at two distinct states: end diastole (top) and end systole (bottom). For clarity, only the three main filament systems of the sarcomere, actin, myosin, and titin filaments, are shown. Highlighted are the regions in the sarcomere proposed to be involved in stress or strain sensing

Fig. 2

Titin domain arrangement in the cardiac sarcomere and connectivity within a mechanical signaling network. Shown is the domain structure of the N2BA-titin isoform, but the splice pathway of the N2B isoform is indicated as well (blue line and text). Highlighted are the regions within titin suggested to be involved in mechanosensing: the NH₂ terminus in the Z-disk, the N2-B and N2-A/PEVK regions in the I-band, and the COOH terminus in the M-band. Thick dashed lines indicate differential splicing. Small numbers indicate titin domain numbering according to Ref. [3]. Abbreviations: ERK2 extracellular signal-regulated kinase-2, FHL1/FHL2 four-and-a-half-LIM-domain protein-1 and -2, FN3 domain fibronectin-type-3-like domain of titin, Ig domain immunoglobulin-like domain of titin, MARPs muscle ankyrin repeat proteins, MEK1/2 MAPK/ERK kinase-1 and -2, MLP muscle LIM protein, MURF1/2 muscle-specific RING-finger proteins-1 and -2, NFAT nuclear factor of activated T cells, Nbr1 neighbor of BRCA1 gene-1, P titin phosphorylation site, PKA cAMP-dependent protein kinase-A, PKC Ca²⁺-dependent protein kinase-Cα, PKG cGMP-dependent protein kinase-G, T-Cap titin-cap (telethonin), us unique sequence of cardiac N2-B region