Human skeletal muscle nebulin sequence encodes a blueprint for thin filament architecture: Sequence motifs and affinity profiles of tandem repeats and terminal SH3

Kuan Wang*, Marie Knipfer, Qi Quan Huang, Ann Van Heerden, Lillian Chi Li Hsu, Gustavo Gutierrez, Xiao Lan Quian, Hansel Stedman

*Corresponding author for this work

Research output: Contribution to journalArticle

124 Scopus citations

Abstract

Analysis of deduced protein sequence and structural motifs of ∼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 ∼150 tandem copies of ∼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.

Original languageEnglish (US)
Pages (from-to)4304-4314
Number of pages11
JournalJournal of Biological Chemistry
Volume271
Issue number8
DOIs
StatePublished - Feb 23 1996

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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