title: Human proteome-scale structural modeling of E2-E3 interactions exploiting interface motifs.
abstract: Ubiquitination is crucial for many cellular processes such as protein degradation, DNA repair, transcription regulation, and cell signaling. Ubiquitin attachment takes place via a sequential enzymatic cascade involving ubiquitin activation (by E1 enzymes), ubiquitin conjugation (by E2 enzymes), and ubiquitin substrate tagging (by E3 enzymes). E3 ligases mediate ubiquitin transfer from E2s to substrates and as such confer substrate specificity. Although E3s can interact and function with numerous E2s, it is still unclear how they choose which E2 to use. Identifying all E2 partners of an E3 is essential for inferring the principles guiding E2 selection by an E3. Here we model the interactions of E3 and E2 proteins in a large, proteome-scale strategy based on interface structural motifs, which allows elucidation of (1) which E3s interact with which E2s in the human ubiquitination pathway and (2) how they interact with each other. Interface analysis of E2-E3 complexes reveals that loop L1 of E2s is critical for binding; the residue in the sixth position in loop L1 is widely utilized as an interface hot spot and appears indispensible for E2 interactions. Other loop L1 residues also confer specificity on the E2-E3 interactions: HECT E3s are in contact with the residue in the second position in loop L1 of E2s, but this is not the case for the RING finger type E3s. Our modeled E2-E3 complexes illuminate how slight sequence variations in E2 residues may contribute to specificity in E3 binding. These findings may be important for discovering drug candidates targeting E3s, which have been implicated in many diseases.
authors.affiliation: Center for Computational Biology and Bioinformatics and College of Engineering, Koc University , Rumelifeneri Yolu, 34450 Sariyer Istanbul, Turkey.
authors.forename: Gozde
authors.initials: G
authors.lastname: Kar
authors.forename: Ozlem
authors.initials: O
authors.lastname: Keskin
authors.forename: Ruth
authors.initials: R
authors.lastname: Nussinov
authors.forename: Attila
authors.initials: A
authors.lastname: Gursoy
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001665:Binding Sites; D003198:Computer Simulation; D030562:Databases, Protein; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D025941:Protein Interaction Mapping; D060066:Protein Interaction Maps; D040901:Proteomics / Q000379:methods*; D016415:Sequence Alignment; D044763:Ubiquitin-Conjugating Enzymes / Q000737:chemistry* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry* / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D044763:Ubiquitin-Conjugating Enzymes; D044767:Ubiquitin-Protein Ligases