Abstract
In striated muscles, molecular filaments are largely composed of long protein chains with extensive arrays of identically folded domains, referred to as “beads-on-a-string”. It remains a largely unresolved question how these domains have developed a unique molecular profile such that each carries out a distinct function without false-positive readout. This study focuses on the M-band segment of the sarcomeric protein titin, which comprises ten identically folded immunoglobulin domains. Comparative analysis of high-resolution structures of six of these domains ‒ M1, M3, M4, M5, M7, and M10 ‒ reveals considerable structural diversity within three distinct loops and a non-conserved pattern of exposed cysteines. Our data allow to structurally interpreting distinct pathological readouts that result from titinopathy-associated variants. Our findings support general principles that could be used to identify individual structural/functional profiles of hundreds of identically folded protein domains within the sarcomere and other densely crowded cellular environments.
Highlights
Sarcomeric filaments in skeletal and cardiac muscles are one of the most complex and ordered cellular structures, which enable them to perform their extraordinary function of alternating contraction and relaxation
Cells were grown at 37 ̊C in lysogeny broth (LB-Lennox) or terrific broth (TB) medium supplemented with the appropriate antibiotics
How false-positive functional readouts from identically folded neighboring domains can be avoided has not been thoroughly investigated to date
Summary
Sarcomeric filaments in skeletal and cardiac muscles are one of the most complex and ordered cellular structures, which enable them to perform their extraordinary function of alternating contraction and relaxation. Various proteinaceous filaments that constitute the sarcomeric ultrastructure are formed either by repetitive arrays of identical subunits, as found in actin and myosin filaments, or by very long polypeptide chains that are composed of extensive arrays of domains with an identical fold [1,2]. These domains often have unique functional fingerprints and the underlying structural basis of these different readouts is yet to be determined. Titin has a molecular weight of more than 3 MDa in its longest isoform and is over 1.5 μm in length, spanning half of a sarcomeric unit from the peripheral Z-disk to the central M-band
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