Multivalency-assisted control of intracellular signaling pathways: application for ubiquitin- dependent N-end rule pathway

Chem Biol. 2009 Feb 27;16(2):121-31. doi: 10.1016/j.chembiol.2009.01.012.

Abstract

Intracellular signaling is often mediated by a family of functionally overlapping signal mediators that contain multiple sites interacting with other proteins or ligands with weak affinity (K(d) > microM). Conjugation of multiple low-affinity ligands into a high-affinity multivalent molecule provides a means to control the entire protein family within a single intracellular pathway. The N-end rule pathway is a ubiquitin (Ub)-dependent proteolytic system where at least four Ub ligases, called N-recognins, have a common domain critical for binding to type 1 (basic) and type 2 (bulky hydrophobic) destabilizing N-terminal residues of substrates as degrons. The recent development of a heterodivalent inhibitor targeting type 1 and type 2 substrate binding sites of the N-recognin family provides new opportunities to manipulate this proteolytic pathway in biochemical and pathophysiological conditions. We overview the N-end rule pathway as an intracellular target for heterodivalent molecules and discuss the basis of thermodynamics and kinetics related to heterodivalent interactions.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Humans
  • Ligands
  • Proteasome Endopeptidase Complex / chemistry
  • Proteasome Endopeptidase Complex / metabolism
  • Proteasome Inhibitors
  • Protein Binding
  • Signal Transduction
  • Substrate Specificity
  • Thermodynamics
  • Ubiquitin / antagonists & inhibitors*
  • Ubiquitin / chemistry
  • Ubiquitin / metabolism*
  • Ubiquitin-Protein Ligases / antagonists & inhibitors*
  • Ubiquitin-Protein Ligases / chemistry
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • Ligands
  • Proteasome Inhibitors
  • Ubiquitin
  • Ubiquitin-Protein Ligases
  • Proteasome Endopeptidase Complex