title: Human skeletal muscle nebulin sequence encodes a blueprint for thin filament architecture. Sequence motifs and affinity profiles of tandem repeats and terminal SH3.
abstract: Analysis of deduced protein sequence and structural motifs of approximately 5500 residues of human fetal skeletal muscle nebulin reveals the design principles of this giant multifunctional protein in the sarcomere. The bulk of the sequence is constructed of approximately 150 tandem copies of approximately 35-residue modules that can be classified into seven types. The majority of these modules form 20 super-repeats, with each super-repeat containing a 7-module set (one of each type in the same order). These super-repeats are further divided into eight segments: with six segments containing adjacent, highly homologous super-repeats, one single repeat segment consisting of 8 nebulin modules of the same type, and a non-repeat segment terminating with a SH3 domain at the C terminus. The interactions of actin, tropomyosin, troponin, and calmodulin with nebulin fragments consisting of either repeating modules or the SH3 domain support its role as a giant actin-binding cofilament of the composite thin filament. Such affinity profiles also suggest that nebulin may bind to tropomyosin and troponin to form a composite calcium-linked regulatory complex on the thin filament. The modular construction, super-repeat structure, and segmental organization of nebulin sequence appear to encode thin filament length, periodicity, insertion, and sarcomere proportion in the resting muscle.
authors.affiliation: Department of Chemistry and Biochemistry, Biochemical Institute and Cell Research Institute, University of Texas, Austin, 78712, USA.
authors.forename: K
authors.initials: K
authors.lastname: Wang
authors.forename: M
authors.initials: M
authors.lastname: Knipfer
authors.forename: Q Q
authors.initials: QQ
authors.lastname: Huang
authors.forename: A
authors.initials: A
authors.lastname: van Heerden
authors.forename: L C
authors.initials: LC
authors.lastname: Hsu
authors.forename: G
authors.initials: G
authors.lastname: Gutierrez
authors.forename: X L
authors.initials: XL
authors.lastname: Quian
authors.forename: H
authors.initials: H
authors.lastname: Stedman
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002645:Chickens; D003001:Cloning, Molecular; D016384:Consensus Sequence; D017124:Conserved Sequence; D018076:DNA, Complementary; D005333:Fetus; D015723:Gene Library; D006801:Humans; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000096:biosynthesis / Q000737:chemistry* / Q000235:genetics*; D018482:Muscle, Skeletal / Q000378:metabolism*; D009838:Oligodeoxyribonucleotides; D016366:Open Reading Frames; D011994:Recombinant Proteins / Q000096:biosynthesis; D012091:Repetitive Sequences, Nucleic Acid; D015183:Restriction Mapping; D017386:Sequence Homology, Amino Acid; D013728:Terminator Regions, Genetic
chemical_list: D018076:DNA, Complementary; D009124:Muscle Proteins; D009838:Oligodeoxyribonucleotides; D011994:Recombinant Proteins; C035620:nebulin