Peptides meet ubiquitin: Simple interactions regulating complex cell signaling

Abstract

The interplay between the ubiquitin proteasome system (UPS) and diverse peptide motifs controls almost every aspect of cell homeostasis. To achieve such an impressive functional diversity nature has evolved hundreds of different peptide motifs that interact with proteins in the UPS and ubiquitin itself to generate an immense network of interactions. Short peptides embedded in proteins are involved in controlling the intracellular levels of proteins as well as in the translation of ubiquitin signals into biochemical events. Therefore, it is not surprising that dysregulation of such interactions is associated with many diseases, including metabolic syndromes, neurodegenerative disorders, and cancer. We review the structural and functional features of peptide motifs interacting with the UPS and their use for generating protein‐protein interaction inhibitors.

Panel of Engineered Ubiquitin Variants Targeting the Family of Human Ubiquitin Interacting Motifs

“…Moreover, competitive phage ELISAs revealed that the majority of the UbVs bound to their cognate UIMs with high apparent affinities, with 57% exhibiting IC 50 values below 100 nM (Table 2 and Figure S2), while Ub.wt recognizes UIMs with affinities in the 100−500 μM range. 11 Although these measurements are only semiquantitative in nature, they represent a good estimation of the enhanced affinity of the engineered UbVs.…”

“…10−12 UBDs typically bind Ub weakly, and virtually all known interactions are mediated through a common face on Ub that encompasses a hydrophobic patch centered on Ile 44 . 11,12 Nonetheless, dynamic NMR studies have shown that interactions between Ub and UBDs are highly diverse and are regulated not only by the structure of the UBD but also by the conformational dynamics of Ub and Ub chains. 13 To date, more than 20 families of diverse UBDs with different folds and binding modes have been described, 10−12 and the simplest of these is the family of Ub-interacting motifs (UIMs), which consist of a single amphipathic α-helix of ∼20 residues that interacts with Ub through a conserved face.…”

“…To a large extent, the signaling function of the Ub code is mediated by the interaction of Ub-conjugated proteins with Ub-binding domains (UBDs) embedded in a variety of proteins with diverse structure, function, and localization. − UBDs typically bind Ub weakly, and virtually all known interactions are mediated through a common face on Ub that encompasses a hydrophobic patch centered on Ile 44 . , Nonetheless, dynamic NMR studies have shown that interactions between Ub and UBDs are highly diverse and are regulated not only by the structure of the UBD but also by the conformational dynamics of Ub and Ub chains …”

“…To date, more than 20 families of diverse UBDs with different folds and binding modes have been described, − and the simplest of these is the family of Ub-interacting motifs (UIMs), which consist of a single amphipathic α-helix of ∼20 residues that interacts with Ub through a conserved face. , Interactions between Ub and UIMs are typically very weak ( K D = 0.1–1 mM), but nonetheless, they have been implicated in many cellular functions, including proteosomal degradation, DNA-damage repair, and endocytosis. − Recently, UIMs have been shown to interact with the Ub-like protein autophagy-related protein 8 (Atg8), suggesting connections between vesicular trafficking and autophagy and a potential role for UIMs in regulating proteostasis …”

Advances in Self-Assembled Peptides as Drug Carriers

“…In addition to this, several peptide sequences with self-assembly potential have been screened from natural proteins. Since then, self-assembled peptides have entered the public eye and become a hot research topic in biomedicine, materials chemistry and other scientific fields [ 5 , 6 , 7 , 8 , 9 ].…”