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Alternative Splicing for Mechanical Resilience: The Softening Effect of Filamin’s Hinge

[+] Author Affiliations
Dennis E. Discher, Colin Johnson

University of Pennsylvania, Philadelphia, PA

Paper No. SBC2007-176751, pp. 789-790; 2 pages
doi:10.1115/SBC2007-176751
From:
  • ASME 2007 Summer Bioengineering Conference
  • ASME 2007 Summer Bioengineering Conference
  • Keystone, Colorado, USA, June 20–24, 2007
  • Conference Sponsors: Bioengineering Division
  • ISBN: 0-7918-4798-5
  • Copyright © 2007 by ASME

abstract

Alternative splicing within proteins is common but not well understood in its influence on protein structure and stability. Filamins are ubiquitous actin-crosslinking proteins with two dozen Immunolgobulin (Ig) repeats and one alternatively-spliced ‘hinge’ that has been hypothesized to add flexibility. The hinge is also predicted to perturb folding. The molecular mechanics of filamins are probed here by AFM-forced extension, with a particular focus on the ∼30 aa hinge between repeats R15 and R16. After re-examining full-length filamin to clarify the single molecule limit for AFM experiments on long chains, short concatemers of (R15-R16)m and (R15-hinge-R16)m were studied by both AFM and solution structural methods. AFM shows that the hinged isoform extends and unfolds at smaller forces (60 pN) than the hinge-less form (80 pN), implying that the alternative splicing introduces a random coil that softens both adjacent domains. Circular Dichroism confirms that the hinge is a random coil, and thermal unfolding in solution suggests a weak destabilization by the hinge. Together with the rate-dependence of forced extension in AFM, the results reveal added resilience as the unfolding transition shifts to longer lengths upon insertion of the alternatively spliced hinge.

Copyright © 2007 by ASME
Topics: Hinges

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