Abstract
Post-translational modifications by ubiquitin and ubiquitin-like proteins (Ubls) have known roles in a myriad of cellular processes. Ubiquitin- and Ubl-binding domains transmit the information conferred by these post-translational modifications by recognizing functional surfaces and, when present, different chain structures. Numerous domains binding to ubiquitin have been characterized and their structures solved. Analogously, motifs selectively interacting with SUMO (small ubiquitin-like modifier) have been identified in several proteins and their role in SUMO-dependent processes investigated. On the other hand, proteins that specifically recognize other Ubl modifications are known only in a few cases. The high sequence identity between NEDD8 and ubiquitin has made the identification of specific NEDD8-binding domains further complicated due to the promiscuity in the recognition by several ubiquitin-binding domains. Two evolutionarily related domains, called CUBAN (cullin-binding domain associating with NEDD8) and CoCUN (cousin of CUBAN), have been recently described. The CUBAN binds monomeric NEDD8 and neddylated cullins, but it also interacts with di-ubiquitin chains. Conversely, the CoCUN domain only binds ubiquitin. CUBAN and CoCUN provide an intriguing example of how nature solved the issue of promiscuity versus selectivity in the recognition of these two highly related molecules. The structural information available to date suggests that the ancestor of CUBAN and CoCUN was a three-helix bundle domain that diversified in KHNYN (KH and NYN domain-containing) and N4BP1 (NEDD4-binding protein-1) by acquiring different features. Indeed, these domains diverged towards two recognition modes, that recall respectively the electrostatic interaction utilized by the E3-ligase RBX1/2 in the interaction with NEDD8, and the hydrophobic features described in the recognition of ubiquitin by CUE (coupling ubiquitin conjugation to ER degradation) domains. Intriguingly, CUBAN and CoCUN domains are only found in KHNYN and N4BP1, respectively, both proteins belonging to the PRORP family whose members are characterized by the combination of protein modules involved in RNA metabolism with domains mediating ubiquitin/NEDD8 recognition. This review recapitulates the current knowledge and recent findings of CUBAN and CoCUN domains and the proteins containing them.
Highlights
Among all the known post-translational modifications, the covalent addition of ubiquitin and ubiquitin-like proteins represents the unique example in which the chemical group modifying the substrate is a protein [1]
The heterogeneity of substrates that are modified by the covalent addition of ubiquitin extends well beyond the limited number of substrates known to be modified by ubiquitin-like proteins (Ubls)
The current state of our knowledge in the field of ubiquitin and ubiquitin-like proteins highlights that, each Ubl family covers selected activities and is conjugated to a restricted substrate panel, we frequently observe the intersection between distinct Ubl families
Summary
Among all the known post-translational modifications, the covalent addition of ubiquitin and ubiquitin-like proteins represents the unique example in which the chemical group modifying the substrate is a protein [1]. Combinations of different families of ubiquitin-binding domains can be arranged in the same ubiquitin receptor, such as the VHS (Vps27p, Hrs and STAM)–UIM couple in STAM1/2 (signal transducing adapter molecule 1/2) proteins and HGS (hepatocyte growth factor-regulated tyrosine kinase substrate) [24,25] and UBAN (Ub-binding domain in ABIN proteins and NEMO)–ZF in NEMO (NF-kappaB essential modulator) [26]. UIM motifs are involved in nonproteolytic processes where they primarily recognize K63-linked ubiquitin chains They are frequently found in membrane-associated ubiquitin receptors that are required for the endocytosis of ligand-activated surface receptors and for the regulation of intracellular trafficking [36], as well as in proteins acting in the DNA damage response [37,38]. The multiplicity of the binding sites and the dynamic regulation of their binding properties further contribute to determining the specificity of ubiquitin-binding modules for ubiquitin
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
