Nebulin
Encyclopedia
Nebulin is an actin
-binding protein which is localized to the I-band of the sarcomeres in skeletal muscle
. It is a very large protein (600-900 kDa) and binds as many as 200 actin monomers. Because its length is proportional to thin filament length, it is believed that nebulin acts as a thin filament "ruler" and regulates thin filament length during sarcomere
assembly. Other functions of nebulin, such as a role in cell signaling
, remain uncertain.
Nebulin has also been shown to regulate actin-myosin interactions by inhibiting ATPase
activity in a calcium
-calmodulin
sensitive manner.
Mutations in nebulin cause some cases of the autosomal recessive disorder nemaline myopathy
.
A second smaller isoform
of nebulin, termed nebulette
, is expressed in cardiac muscle
.
of nebulin was determined by NMR
. The SH3 domain from nebulin is composed of 60 amino acid residues, of which 30 percent is in the beta sheet
secondary struture (7 strands; 18 residues).
models for nebulin have been developed to better understand its in vivo function. Bang and colleagues demonstrated that nebulin-knockout mice die postnatally, have reduced thin filament length, and impaired contractile function
. Postnatal sarcomere
disorganization and degeneration occurred rapidly in these mice, indicating the nebulin is essential for maintaining the structural integrity of myofibril
s. Witt and colleagues had similar results in their mice, which also died postnatally with reduced thin filament length and contractile function. These nebulin-knockout mice are being investigated as animal model
s of nemaline myopathy
.
Actin
Actin is a globular, roughly 42-kDa moonlighting protein found in all eukaryotic cells where it may be present at concentrations of over 100 μM. It is also one of the most highly-conserved proteins, differing by no more than 20% in species as diverse as algae and humans...
-binding protein which is localized to the I-band of the sarcomeres in skeletal muscle
Skeletal muscle
Skeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system- i.e. it is voluntarily controlled. It is one of three major muscle types, the others being cardiac and smooth muscle...
. It is a very large protein (600-900 kDa) and binds as many as 200 actin monomers. Because its length is proportional to thin filament length, it is believed that nebulin acts as a thin filament "ruler" and regulates thin filament length during sarcomere
Sarcomere
A sarcomere is the basic unit of a muscle. Muscles are composed of tubular muscle cells . Muscle cells are composed of tubular myofibrils. Myofibrils are composed of repeating sections of sarcomeres, which appear under the microscope as dark and light bands...
assembly. Other functions of nebulin, such as a role in cell signaling
Cell signaling
Cell signaling is part of a complex system of communication that governs basic cellular activities and coordinates cell actions. The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity as well as normal tissue...
, remain uncertain.
Nebulin has also been shown to regulate actin-myosin interactions by inhibiting ATPase
ATPase
ATPases are a class of enzymes that catalyze the decomposition of adenosine triphosphate into adenosine diphosphate and a free phosphate ion. This dephosphorylation reaction releases energy, which the enzyme harnesses to drive other chemical reactions that would not otherwise occur...
activity in a calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
-calmodulin
Calmodulin
Calmodulin is a calcium-binding protein expressed in all eukaryotic cells...
sensitive manner.
Mutations in nebulin cause some cases of the autosomal recessive disorder nemaline myopathy
Nemaline myopathy
Nemaline myopathy is a congenital, hereditary neuromuscular disorder that causes muscle weakness, generally nonprogressive, of varying severity....
.
A second smaller isoform
Protein isoform
A protein isoform is any of several different forms of the same protein. Different forms of a protein may be produced from related genes, or may arise from the same gene by alternative splicing. A large number of isoforms are caused by single-nucleotide polymorphisms or SNPs, small genetic...
of nebulin, termed nebulette
Nebulette
Nebulette is an isoform of the protein nebulin. While nebulin is expressed preferentially in skeletal muscle, nebulette is expressed in cardiac muscle. Nebulette was identified in 1995 by Moncman and Wang using primary cultures of chicken embryonic cardiomyocytes by immunoprecipitations with...
, is expressed in cardiac muscle
Cardiac muscle
Cardiac muscle is a type of involuntary striated muscle found in the walls and histologic foundation of the heart, specifically the myocardium. Cardiac muscle is one of three major types of muscle, the others being skeletal and smooth muscle...
.
Structure
The structure of the SH3 domainSH3 domain
The SRC Homology 3 Domain is a small protein domain of about 60 amino acids residues first identified as a conserved sequence in the viral adaptor protein v-Crk and the non-catalytic parts of enzymes such as phospholipase and several cytoplasmic tyrosine kinases such as Abl and Src...
of nebulin was determined by NMR
Protein nuclear magnetic resonance spectroscopy
Nuclear magnetic resonance spectroscopy of proteins is a field of structural biology in which NMR spectroscopy is used to obtain information about the structure and dynamics of proteins. The field was pioneered by Richard R. Ernst and Kurt Wüthrich, among others...
. The SH3 domain from nebulin is composed of 60 amino acid residues, of which 30 percent is in the beta sheet
Beta sheet
The β sheet is the second form of regular secondary structure in proteins, only somewhat less common than the alpha helix. Beta sheets consist of beta strands connected laterally by at least two or three backbone hydrogen bonds, forming a generally twisted, pleated sheet...
secondary struture (7 strands; 18 residues).
Knockout phenotype
As of 2007, two knockout mouseKnockout mouse
A knockout mouse is a genetically engineered mouse in which researchers have inactivated, or "knocked out," an existing gene by replacing it or disrupting it with an artificial piece of DNA...
models for nebulin have been developed to better understand its in vivo function. Bang and colleagues demonstrated that nebulin-knockout mice die postnatally, have reduced thin filament length, and impaired contractile function
Muscle contraction
Muscle fiber generates tension through the action of actin and myosin cross-bridge cycling. While under tension, the muscle may lengthen, shorten, or remain the same...
. Postnatal sarcomere
Sarcomere
A sarcomere is the basic unit of a muscle. Muscles are composed of tubular muscle cells . Muscle cells are composed of tubular myofibrils. Myofibrils are composed of repeating sections of sarcomeres, which appear under the microscope as dark and light bands...
disorganization and degeneration occurred rapidly in these mice, indicating the nebulin is essential for maintaining the structural integrity of myofibril
Myofibril
A myofibril is a basic unit of a muscle. Muscles are composed of tubular cells called myocytes or myofibers. Myofibers are composed of tubular myofibrils. Myofibrils are composed of long proteins such as actin, myosin, and titin, and other proteins that hold them together...
s. Witt and colleagues had similar results in their mice, which also died postnatally with reduced thin filament length and contractile function. These nebulin-knockout mice are being investigated as animal model
Animal model
An animal model is a living, non-human animal used during the research and investigation of human disease, for the purpose of better understanding the disease without the added risk of causing harm to an actual human being during the process...
s of nemaline myopathy
Nemaline myopathy
Nemaline myopathy is a congenital, hereditary neuromuscular disorder that causes muscle weakness, generally nonprogressive, of varying severity....
.