Multivalency-assisted control of intracellular signaling pathways: application for ubiquitin- dependent N-end rule pathway.
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.
Sriram
Shashikanth M
SM
Center for Pharmacogenetics and Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Banerjee
Rajkumar
R
Kane
Ravi S
RS
Kwon
Yong Tae
YT
D000818:Animals; D006801:Humans; D008024:Ligands; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000378:metabolism; D061988:Proteasome Inhibitors; D011485:Protein Binding; D015398:Signal Transduction; D013379:Substrate Specificity; D013816:Thermodynamics; D025801:Ubiquitin / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*
D008024:Ligands; D061988:Proteasome Inhibitors; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex