Structural Dynamic Heterogeneity of Polyubiquitin Subunits Affects Phosphorylation Susceptibility

Biochemistry. 2021 Mar 2;60(8):573-583. doi: 10.1021/acs.biochem.0c00619. Epub 2021 Feb 22.

Abstract

Polyubiquitin is a multifunctional protein tag formed by the covalent conjugation of ubiquitin molecules. Due to the high rigidity of the ubiquitin fold, the ubiquitin moieties in a polyubiquitin chain appear to be structurally equivalent to each other. It is therefore unclear how a specific ubiquitin moiety in a chain may be preferentially recognized by some proteins, such as the kinase PINK1. Here we show that there is structural dynamic heterogeneity in the two ubiquitin moieties of K48-linked diubiquitin by NMR spectroscopic analyses. Our analyses capture subunit-asymmetric structural fluctuations that are not directly related to the closed-to-open transition of the two ubiquitin moieties in diubiquitin. Strikingly, these newly identified heterogeneous structural fluctuations may be linked to an increase in susceptibility to phosphorylation by PINK1. Coupled with the fact that there are almost no differences in static tertiary structure among ubiquitin moieties in a chain, the observed subunit-specific structural fluctuations may be an important factor that distinguishes individual ubiquitin moieties in a chain, thereby aiding both efficiency and specificity in post-translational modifications.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Models, Molecular
  • Phosphorylation
  • Polyubiquitin / chemistry*
  • Polyubiquitin / metabolism
  • Protein Binding
  • Protein Conformation
  • Protein Kinases / chemistry*
  • Protein Kinases / metabolism
  • Protein Processing, Post-Translational*

Substances

  • Polyubiquitin
  • Protein Kinases
  • PTEN-induced putative kinase