Nebulin, a multi-functional giant

Abstract

Efficient muscle contraction in skeletal muscle is predicated on the regulation of actin filament lengths. In one long-standing model that was prominent for decades, the giant protein nebulin was proposed to function as a 'molecular ruler' to specify the lengths of the thin filaments. This theory was questioned by many observations, including experiments in which the length of nebulin was manipulated in skeletal myocytes; this approach revealed that nebulin functions to stabilize filamentous actin, allowing thin filaments to reach mature lengths. In addition, more recent data, mostly from in vivo models and identification of new interacting partners, have provided evidence that nebulin is not merely a structural protein. Nebulin plays a role in numerous cellular processes including regulation of muscle contraction, Z-disc formation, and myofibril organization and assembly.

Arthrogryposis and pterygia as lethal end manifestations of genetically defined congenital myopathies

“…It is composed of repetitive elements that have actin‐ and tropomyosin‐binding motifs. In addition to being a structural protein, nebulin also contributes to proper muscle function (Chu, Gregorio, & Pappas, ) Although NEB variants are most commonly associated with autosomal‐recessive nemaline myopathy (Lehtokari et al, ), other less common entities have been described (Romero et al, ; Scoto et al, ). Thus in the absence of muscle biopsy for the typical pathologic features of NM, it is difficult to characterize cases 1 and 2 as SCNM.…”

The sarcomeric cytoskeleton: from molecules to motion

“…How these changes are therefore transmitted from the I-and A-band regions of the thin filament to the Z-disk remains a mystery. Possibly, other thin-filament-associated proteins play a role, and the giant nebulin and its small cardiac homologue, nebulette, would be plausible candidates, as they span from the Z-disk into the I-band (see review by Chu et al, 2016, in this issue; see also below). A structural model of the core Z-disk that reconciles known protein-binding sites and mapped protein and epitope positions, but not the axial repeat observed in EM, is shown in Fig.…”

“…This concept is currently under intense scrutiny because of the mismatch of the pointed-end capping protein tropomodulin and the N-terminus of nebulin, which do not coincide. Accordingly, alternative explanations via a 'two-segment' model that challenge the paradigm of the nebulin controller have been proposed by the team of V. Fowler (Castillo et al, 2009;Fowler et al, 2006;Gokhin and Fowler, 2013;Littlefield and Fowler, 2008) and are further discussed in the review by Chu et al (2016) in this issue.…”

Nebulette is a powerful cytolinker organizing desmin and actin in mouse hearts

“…These in turn are connected at both ends by elastic titin molecules, the largest protein in muscle, exhibiting a length of 2 μm. Nebulin, the second-largest sarcomeric protein (∼900 kDa), stabilizes a large core of the actin filaments (Chu et al , 2016). In support of these long range–acting factors, nebulette, the smaller and functionally related protein, is thought to stabilize a shorter core of the actin filaments in cardiac cells (Littlefield and Fowler, 2008).…”