Ubiquitin is an 8.5-kDa polypeptide that exists in all eukaryotic cells and acts as a tag in post-translational modification of proteins. Ubiquitin is a β-grasp fold protein consisting of a 3.5-turn α-helix, a short 310 helix against a five-strand mixed β-sheet and seven reverse turns. Ubiquitin is highly conserved throughout eukaryote evolution and interchangeable and universal in different species. In mammals, ubiquitin is encoded by 4 different genes. UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. The UBB and UBC genes code for polyubiquitin precursor proteins.
In addition to ubiquitin, ubiquitin-like proteins (UBLs), which have similar three-dimensional structures and related sequences to ubiquitin, can also be conjugated to and alter the function of substrate proteins. Each UBL and ubiquitin have the same three-dimensional core structure-the β-grasp fold. With the discovery of ubiquitin, more than a dozen UBLs have been identified, such as small ubiquitin-like modifier (SUMO), neural precursor cell expressed and developmentally down-regulated 8 (NEDD8), interferon-stimulated gene 15 (ISG15), human leukocyte antigen F locus adjacent transcription 10 (FAT10), ubiquitin-fold modifier 1 (UFM1), ubiquitin-related modifier 1 (URM1), autophagy-related protein 12 (ATG12), autophagy-related protein 8 (ATG8), Finkel-Biskis-Reilly murine sarcoma virus (FBR-MuSV) ubiquitously expressed (FUBI) and ubiquitin-like protein 5 (UBL5). UBLs such as SUMO, ISG15, Nedd8 and Atg8 act as key regulators of many cellular processes, including transcription, DNA repair, signal transduction, autophagy and cell cycle control.
Although SUMOs exhibit a modification regulation process like ubiquitination, they have completely opposite functions. They increase the stability of substrate proteins through covalently binding to corresponding substrates to further participate in many cellular processes. There are four SUMOs in mammalian cells. SUMO-1, SUMO-2 and SUMO-3 have certain homologous amino acid sequences, and SUMO-2 and SUMO-3 have high sequence similarity. SUMO-1 is involved in nuclear transport, nuclear composition, signal transduction, transcription regulation, chromatin remodeling, DNA repair, ribosome composition and other processes. SUMO-2 and SUMO-3 only bind to substrates to perform corresponding functions after cell are stimulated. SUMO-4 may be a regulatory molecule involved in cellular responses under pathological conditions. Lack of translational modification of SUMOs can lead to cardiovascular disease, neurodegenerative disease, kidney disease and cancers.