Stabilization of the spectrin-like domains of nesprin-1α by the evolutionarily conserved "adaptive" domain

Zhixia Zhong, Siwei A. Chang, Agnieszka Kalinowski, Katherine L. Wilson, Kris Noel Dahl

Research output: Contribution to journalArticle

Abstract

Nesprins are located at the outer and inner membranes of the nuclear envelope and help link the cytoskeleton to the nucleoskeleton. Nesprin-1α, located at the inner nuclear membrane, binds to A-type lamins and emerin and has homology to spectrin-repeat proteins. However, the mechanical and thermodynamic properties of the spectrin-like repeats (SLRs) of nesprin-1α and the potential structural contributions of the unique central domain were untested. In other spectrin superfamily proteins, tandem spectrin-repeat domains undergo cooperatively coupled folding and unfolding. We hypothesized that the large central domain, which interrupts SLRs and is conserved in other nesprin isoforms, might confer unique structural properties. To test this model we measured the thermal unfolding of nesprin-1α fragments using circular dichroism and dynamic light scattering. The SLRs in nesprin-1α were found to have structural and thermodynamic properties typical of spectrins. The central domain had relatively little secondary structure as an isolated fragment, but significantly stabilized larger SLR-containing molecules by increasing their overall helicity, thermal stability and cooperativity of folding. We suggest this domain, now termed the "adaptive" domain (AD), also strengthens dimerization and inhibits unfolding. Further engineering of the isolated AD, and AD-containing nesprin molecules, may yield new information about the higher-order association of cooperative protein motifs.

Original languageEnglish (US)
Pages (from-to)139-150
Number of pages12
JournalCellular and Molecular Bioengineering
Volume3
Issue number2
DOIs
StatePublished - Jun 1 2010

Keywords

  • Emerin
  • LINC complex
  • Laminopathy
  • Nuclear envelope
  • Nuclear mechanics
  • Spectrin repeat

ASJC Scopus subject areas

  • Modeling and Simulation
  • Biochemistry, Genetics and Molecular Biology(all)

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