The giant protein titin: a regulatory node that integrates myocyte signaling pathways

Abstract

Titin, the largest protein in the human body, is well known as a molecular spring in muscle cells and scaffold protein aiding myofibrillar assembly. However, recent evidence has established another important role for titin: that of a regulatory node integrating, and perhaps coordinating, diverse signaling pathways, particularly in cardiomyocytes. We review key findings within this emerging field, including those related to phosphorylation of the titin springs, and also discuss how titin participates in hypertrophic gene regulation and protein quality control.

FIGURE 1.

Layout of titin in the half-sarcomere and atomic structures of titin domains available to date. Shown are two strands of the cardiac N2BA titin isoform. Atomic structures were obtained from the Protein Data Bank; for original references, see the text. X-Ray indicates that the structure was resolved by x-ray crystallography; NMR indicates that the structure was resolved by solution nuclear magnetic resonance spectroscopy. Titin domain nomenclature is according to Ref. ; note that Ig domain I91 is often called I27 elsewhere in the literature. Z, I, A, and M refer to Z-disk, I-band, A-band, and M-band titin location, respectively. The titin segments are as follows. Ig is the immunoglobulin-like domain region; N2-B is the cardiac-specific region encoded by human titin exon 49; N2-A is the I-band region encoded by human titin exons 102–109; PEVK is the unique sequence (>70% Pro, Glu, Val, and Lys residues); and the FN3-like domain is the fibronectin type 3-like domain.

FIGURE 2.

Cardiomyocyte signaling pathways converging on titin. The schematic shows the domain architecture of cardiac titin isoforms (N2B and N2BA) and binding partners that link titin to hypertrophic signaling pathways or protein quality control mechanisms. The inset demonstrates that titin-based PT can be variably tuned either by reversible phosphorylation or by altering the N2BA/N2B titin isoform expression ratio. AC, adenylyl cyclase; ANP, atrial natriuretic peptide; AngII, angiotensin II; βAR, β-adrenergic receptor; BNP, brain natriuretic peptide; CNP, C-type natriuretic peptide; ET-1, endothelin-1; G, small G-protein; GPCR, G-protein-coupled receptor; MLP, muscle LIM protein; NFAT, nuclear factor of activated T-cells; P, titin phosphorylation site; pGC, particulate guanylyl cyclase; PLC, phospholipase C; sGC, soluble guanylyl cyclase; us, unique sequence of the cardiac N2-B region.