In eukaryotes, ubiquitin and other ubiquitin-like (Ub/UBL) modifications share a similar three-step thioester cascade process catalyzed by E1s (ubiquitin-activating enzymes), E2s (ubiquitin-conjugating enzymes) and E3s (ubiquitin-protein ligases) (Kerscher et al., 2006). The process of Ub/UBL conjugation is reversed by DUBs (deubiquitinating enzymes), which could remove the Ub/UBL from modified proteins (Nijman et al., 2005; Reyes-Turcu et al., 2009). Moreover, UBDs (ubiquitin-binding domain containing proteins) can selectively recognize monoubiquitin and ubiquitin chains with different linkages and lengths to control various cellular functions in vivo (Husnjak et al., 2012). Besides, ULDs (ubiquitin like domains) are also identified as important integral elements of a large variety of protein families (Upadhya et al., 2003). Owe to the complexity of ubiquitin signal formation and its corresponding recognition mechanism, ubiquitination performs various cellular and physiological functions.

    The released iUUCD (integrated annotations for Ubiquitin and Ubiquitin-like Conjugation Database, ver 2.0) is an updated systematic resource for ubiquitin and ubiquitin-like conjugations. 27 E1s, 109 E2s, 1,153 E3s, 164 DUBs, 396 UBDs and 183 ULDs were collected from scientific literatures and classified into 1, 4, 23, 8, 27, 11 families, respectively. The newly release added 6 new families for E2, E3 and DUB enzymes, as well as a hierarchical classification for UBD and ULD families. Specially, detailed annotations for all these proteins were integrated from additional 68 public databases in 11 aspects as follows: (i) Cancer Mutation, including ICGC, COSMIC, TCGA, CGAP and IntOGen; (ii) Single Nucleotide Polymorphism (SNP), such as dbSNP; (iii) mRNA Expression, including GEO, ArrayExpress, GXD, FFGED, TCGA, ICGC, COSMIC, HUMAN PROTEOME MAP and The Human Protein Atlas; (iv) DNA & RNA Element, including UTRdb, AREsite, JASPAR CORE, circBase, circRNADb, CircNet, Circ2Traits, miRTarBase, microRNA.org, TRANSFAC, miRWalk, TargetScan, miRecords, RepTar, miRNAMap, SomamiR DB 2.0, miRcode, RAID v2.0 and LncRNADisease; (v) Protein-protein Interaction, including IID, iRefIndex, PINA, HINT, Mentha, SZDB and InWeb_IM; (vi) Protein 3D Structure, including PDB, MMDB and SCOP; (vii) Disease-associated Variation, including ClinVar, OMIM, GWASdb and GWAS CENTRAL; (viii) Drug-target Relation, including DrugBank, TTD, KPID, CARLSBAD, SuperTarget, GRAC and PDTD; (ix) Post-translational Modifications (PTMs), including CPLM, dbPAF, dbPPT, phosSNP, PhosphositePlus, Phospho.ELM, dbPTM, PHOSIDA, BioGRID, HPRD, UniProt, O-GlycBase, PhosphoBase and mUbiSiDa; (x) DNA Methylation, including MethyCancer, TCGA, ICGC and COSMIC; (xi) Protein Expression/Proteomics, including The Human Protein Atlas, Human Proteome Map and GPMDB. All in all, from 148 eukaryotic species, 136,512 proteins were identified and annotated as unique entries in iUUCD.