Structure/function implications in a dynamic complex of the intrinsically disordered Sic1 with the Cdc4 subunit of an SCF ubiquitin ligase

Tanja Mittag, Joseph Marsh, Alexander Grishaev, Stephen Orlicky, Hong Lin, Frank Sicheri, Mike Tyers, Julie D Forman-Kay

Research output: Contribution to journalArticlepeer-review

Abstract

Intrinsically disordered proteins can form highly dynamic complexes with partner proteins. One such dynamic complex involves the intrinsically disordered Sic1 with its partner Cdc4 in regulation of yeast cell cycle progression. Phosphorylation of six N-terminal Sic1 sites leads to equilibrium engagement of each phosphorylation site with the primary binding pocket in Cdc4, the substrate recognition subunit of a ubiquitin ligase. ENSEMBLE calculations using experimental nuclear magnetic resonance and small-angle X-ray scattering data reveal significant transient structure in both phosphorylation states of the isolated ensembles (Sic1 and pSic1) that modulates their electrostatic potential, suggesting a structural basis for the proposed strong contribution of electrostatics to binding. A structural model of the dynamic pSic1-Cdc4 complex demonstrates the spatial arrangements in the ubiquitin ligase complex. These results provide a physical picture of a protein that is predominantly disordered in both its free and bound states, enabling aspects of its structure/function relationship to be elucidated.
Original languageEnglish
Pages (from-to)494-506
Number of pages13
JournalStructure
Volume18
Issue number4
DOIs
Publication statusPublished - 14 Mar 2010

Keywords

  • Cell Cycle Proteins
  • Crystallography, X-Ray
  • Cyclin-Dependent Kinase Inhibitor Proteins
  • F-Box Proteins
  • Magnetic Resonance Spectroscopy
  • Molecular Conformation
  • Phosphorylation
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • SKP Cullin F-Box Protein Ligases
  • Saccharomyces cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Scattering, Radiation
  • Static Electricity
  • Structure-Activity Relationship
  • Substrate Specificity
  • Threonine
  • Ubiquitin-Protein Ligases

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