Nebulin: big protein with big responsibilities

Abstract

Nebulin, encoded by NEB, is a giant skeletal muscle protein of about 6669 amino acids which forms an integral part of the sarcomeric thin filament. In recent years, the nebula around this protein has been largely lifted resulting in the discovery that nebulin is critical for a number of tasks in skeletal muscle. In this review, we firstly discussed nebulin's role as a structural component of the thin filament and the Z-disk, regulating the length and the mechanical properties of the thin filament as well as providing stability to myofibrils by interacting with structural proteins within the Z-disk. Secondly, we reviewed nebulin's involvement in the regulation of muscle contraction, cross-bridge cycling kinetics, Ca 2+-homeostasis and excitation contraction (EC) coupling. While its role in Ca 2+-homeostasis and EC coupling is still poorly understood, a large number of studies have helped to improve our knowledge on how nebulin affects skeletal muscle contractile mechanics. These studies suggest that nebulin affects the number of force generating actin-myosin cross-bridges and may also affect the force that each cross-bridge produces. It may exert this effect by interacting directly with actin and myosin and/or indirectly by potentially changing the localisation and function of the regulatory complex (troponin and tropomyosin). Besides unravelling the biology of nebulin, these studies are particularly helpful in understanding the patho-mechanism of myopathies caused by NEB mutations, providing knowledge which constitutes the critical first step towards the development of therapeutic interventions. Currently, effective treatments are not available, although a number of therapeutic strategies are being investigated.

A Homozygous Deep Intronic Mutation Alters the Splicing of Nebulin Gene in a Patient With Nemaline Myopathy

“…These shortened transcripts are very likely to be non-functional since they lacked the C terminal portion of the gene which encodes the SH3 domain ( 59 ). The binding of multiple essential partners of nebulin have been found to be regulated by this highly conserve serine-rich SH3 domain ( 39 ). Among those we found are α-actinin, myopalladin, CapZ, titin, and many other major players of the muscle sarcomere ( Figure 1 ).…”

“…Exons 63–66, 82–105, 143–144, and 166–177 are alternative spliced exons, and exon 143 and 144 have not been detected in the same transcript ( 37 , 38 ). The structure of the NEB protein is composed of simple motif repeats, of a central super repeat regions SR1 to SR22 made up of seven simple repeats each, and of a serine-rich SH3 domain in C-terminal ( 39 ). The repeat modules contain the essential conserved binding motifs for actin.…”

“…Binding partners are written in blue. Adapted from Yuen and Ottenheijm ( 39 ), http://creativecommons.org/licenses/by/4.0/ .…”

Variants in NEB and RIF1 genes on chr2q23 are associated with skeletal muscle index in Koreans: genome-wide association study

“…The NEB gene encodes for nebulin, a giant protein component of the cytoskeletal matrix that coexists with the thick and thin filaments within the sarcomeres of skeletal muscle 22 . Its critical role in muscle function became apparent when mutations in NEB were associated with autosomal recessive nemaline myopathy, a disease characterized by generalized skeletal muscle weakness and the presence of electron-dense protein accumulations (nemaline rods) seen on patient muscle biopsy examination 23 , 24 . Although the important role of NEB for skeletal muscle is well known, to our knowledge, variants in NEB have not been reported in prior GWA studies of muscle-related phenotypes (whole-body or appendicular lean body mass) through a review of the GWAS catalog ( https://www.ebi.ac.uk/gwas/genes/NEB ).…”

Targeting ERK-Hippo Interplay in Cancer Therapy

“…Interaction of ERK and MST kinase with MBP sheds new light on the role of these kinases in the regulation of neuron cells and immunity function. Nebulin binds and stabilizes F-actin filaments and is responsible for the structural integrity of the cell [36]. Role for MST kinase in mechanotransduction was already characterized however participation of ERK kinase in this process remains obscure [37].…”