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.The specialized cytoskeleton of striated muscle cells consists of highly ordered structures, the sarcomeres, which are built of myosin, actin, and titin filaments (Fig. 1), along with a plethora of other structural and regulatory proteins. The cytoskeleton is no longer seen as a static skeleton that fixes each cellular component but as a dynamic and sensitive cellular organizer that responds to various extracellular clues. Muscle cells are no exception to this; however, some responses to external signals are unique to myocytes due to the specialized protein composition and ordered arrangement of the sarcomeres. In this minireview, we first provide general information on the structure and function of the giant muscle protein titin (also known as connectin) and then focus on the dynamic role of titin as an important regulatory node in the sarcomeric cytoskeleton. Special attention is paid to emerging evidence suggesting that phosphorylation by various protein kinases alters titin function.

Atomic model of the human cardiac muscle myosin filament

“…The 11-domain repeats each follow the sequence (N)-Ig-Fn3-Fn3-Ig-Fn3-Fn3-Fn3-Ig-Fn3-Fn3-Fn3-(C). The axial distance between each large superrepeat copy is 429 Å, and this series ends at the edge of the bare zone (22)(23)(24)(25). The 11 copies of the 11-domain large superrepeat of titin cover both the C zone and the P zone (Fig.…”

From signal transduction to signal interpretation: An alternative model for the molecular function of insulin receptor substrates

“…Inclusion of filamins into specific protein complexes forming on IRS proteins might therefore underlie insulin's ability to control actin remodelling. Titin is the largest protein in the human body and functions as a molecular spring in muscle cells (Kruger and Linke, 2011). Although phosphorylation sites have been detected in several portions of titin and it has been suggested that titin could be a regulatory node for co-ordination of signalling pathways dependent on PKA, PKG and PKC no relation to insulin action has been described so far.…”

Label-free Quantitative Protein Profiling of vastus lateralis Muscle During Human Aging

“…Myosin, the motor protein for muscular contraction, is a hexameric protein that consists of two heavy chain subunits (which myosin-1 belongs to), two alkali light chain subunits and two regulatory light chain subunits (which myosin light chain 1/3 belongs to). Titin is essential for myofibrillar assembly by connecting the Z line to the M line in the sarcomere, and represents also a regulatory node for various transduction pathways (38). The function of the easily releasable proteins remains unknown, although they were suggested to represent intermediate products in the turnover of myofibrillar proteins (39,17).…”