Structural and Functional Studies of Titin's fn3 Modules Reveal Conserved Surface Patterns and Binding to Myosin S1 - A Possible Role in the Frank-Starling Mechanism of the Heart

Claudia Muhle-Goll, Michael Habeck, Olivier Cazorla, Michael Nilges, Siegfried Labeit, Henk Granzier

Research output: Contribution to journalArticlepeer-review

74 Scopus citations

Abstract

The A-band part of titin, a striated-muscle specific protein spanning from the Z-line to the M-line, mainly consists of a well-ordered super-repeat array of immunoglobulin-like and fibronectin-type III (fn3)-like domains. Since it has been suspected that the fn3 domains might represent titin's binding sites to myosin, we have developed structural models for all of titin's 132 fn3-like domains. A subset of eight experimentally determined fn3 structures from a range of proteins, including titin itself, was used as homology templates. After grouping the models according to their position within the super-repeat segment of the central A-band titin region, we analyzed the models with respect to side-chain conservation. This showed that conserved residues form an extensive surface pattern predominantly at one side of the domains, whereas domains outside the central C-zone super-repeat region show generally less conserved surfaces. Since the conserved surface residues may function as protein-binding sites, we experimentally studied the binding properties of expressed multi-domain fn3 fragments. This revealed that fn3 fragments specifically bind to the sub-fragment 1 of myosin. We also measured the effect of fn3 fragments on the contractile properties of single cardiac myocytes. At sub-maximal Ca2+ concentrations, fn3 fragments significantly enhance active tension. This effect is most pronounced at short sarcomere length, and as a result the length-dependence of Ca2+ activation is reduced. A model of how titin's fn3-like domains may influence actomyosin interaction is proposed.

Original languageEnglish (US)
Pages (from-to)431-447
Number of pages17
JournalJournal of Molecular Biology
Volume313
Issue number2
DOIs
StatePublished - Oct 19 2001
Externally publishedYes

Keywords

  • Fibronectin type III
  • Molecular modeling
  • Muscle contraction
  • Striated muscle
  • Titin

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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