Muscle giants: molecular scaffolds in sarcomerogenesis.
Myofibrillogenesis in striated muscles is a highly complex process that depends on the coordinated assembly and integration of a large number of contractile, cytoskeletal, and signaling proteins into regular arrays, the sarcomeres. It is also associated with the stereotypical assembly of the sarcoplasmic reticulum and the transverse tubules around each sarcomere. Three giant, muscle-specific proteins, titin (3-4 MDa), nebulin (600-800 kDa), and obscurin (approximately 720-900 kDa), have been proposed to play important roles in the assembly and stabilization of sarcomeres. There is a large amount of data showing that each of these molecules interacts with several to many different protein ligands, regulating their activity and localizing them to particular sites within or surrounding sarcomeres. Consistent with this, mutations in each of these proteins have been linked to skeletal and cardiac myopathies or to muscular dystrophies. The evidence that any of them plays a role as a "molecular template," "molecular blueprint," or "molecular ruler" is less definitive, however. Here we review the structure and function of titin, nebulin, and obscurin, with the literature supporting a role for them as scaffolding molecules and the contradictory evidence regarding their roles as molecular guides in sarcomerogenesis.
Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA. akons001@umaryland.edu
Aikaterini
A
Kontrogianni-Konstantopoulos
Maegen A
MA
Ackermann
Amber L
AL
Bowman
Solomon V
SV
Yap
Robert J
RJ
Bloch
D000818:Animals; D064211:Connectin; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000502:physiology; D006801:Humans; D009124:Muscle Proteins / Q000737:chemistry / Q000502:physiology*; D009132:Muscles / Q000502:physiology* / Q000648:ultrastructure; D009135:Muscular Diseases / Q000503:physiopathology; D009210:Myofibrils / Q000502:physiology; D011494:Protein Kinases / Q000737:chemistry / Q000502:physiology; D017346:Protein Serine-Threonine Kinases; D064067:Rho Guanine Nucleotide Exchange Factors; D012518:Sarcomeres / Q000502:physiology*
D064211:Connectin; D020662:Guanine Nucleotide Exchange Factors; D009124:Muscle Proteins; D064067:Rho Guanine Nucleotide Exchange Factors; C577285:TTN protein, human; C035620:nebulin; D011494:Protein Kinases; C578224:OBSCN protein, human; D017346:Protein Serine-Threonine Kinases