Ubiquitin-like proteins (UBLs) are a household of small proteins concerned in post-translational modification of different proteins in a cell, normally with a regulatory perform. The UBL protein household derives its identify from the primary member of the category to be found, ubiquitin (Ub), greatest identified for its function in regulating protein degradation by means of covalent modification of different proteins. Following the invention of ubiquitin, many extra evolutionarily associated members of the group had been described, involving parallel regulatory processes and related chemistry. UBLs are concerned in a broadly various array of mobile capabilities together with autophagy, protein trafficking, irritation and immune responses, transcription, DNA restore, RNA splicing, and mobile differentiation.[1][2][3]
Contents
Discovery[edit]
Ubiquitin itself was first found within the Nineteen Seventies and initially named “ubiquitous immunopoietic polypeptide”.[4] Subsequently, different proteins with sequence similarity to ubiquitin had been sometimes reported within the literature, however the first proven to share the important thing characteristic of covalent protein modification was ISG15, found in 1987.[5] A succession of experiences within the mid Nineties is acknowledged as a turning level within the subject,[6] with the invention of SUMO (small ubiquitin-like modifier, often known as Sentrin or SENP1) reported across the similar time by quite a lot of investigators in 1996,[7] NEDD8 in 1997,[8] and Apg12 in 1998.[9] A scientific survey has since recognized over 10,000 distinct genes for ubiquitin or ubiquitin-like proteins represented in eukaryotic genomes.[10]
Construction and classification[edit]
Members of the UBL household are small, non-enzymatic proteins that share a typical construction exemplified by ubiquitin, which has 76 amino acid residues organized right into a “beta-grasp” protein fold consisting of a five-strand antiparallel beta sheet surrounding an alpha helix.[1][11][12] The beta-grasp fold is broadly distributed in different proteins of each eukaryotic and prokaryotic origin.[13] Collectively, ubiquitin and ubiquitin-like proteins are generally known as “ubiquitons”.[3]
UBLs could be divided into two classes relying on their means to be covalently conjugated to different molecules. UBLs which can be able to conjugation (generally often known as Kind I) have a attribute sequence motif consisting of 1 to 2 glycine residues on the C-terminus, by means of which covalent conjugation happens. Sometimes, UBLs are expressed as inactive precursors and have to be activated by proteolysis of the C-terminus to show the lively glycine.[1][12] Virtually all such UBLs are finally linked to a different protein, however there’s no less than one exception; ATG8 is linked to phosphatidylethanolamine.[1] UBLs that don’t exhibit covalent conjugation (Kind II) usually happen as protein domains genetically fused to different domains in a single bigger polypeptide chain, and could also be proteolytically processed to launch the UBL area[1] or might perform as protein-protein interplay domains.[11] UBL domains of bigger proteins are generally often known as UBX domains.[14]
Distribution[edit]
Ubiquitin is, as its identify suggests, ubiquitous in eukaryotes; it’s historically thought-about to be absent in micro organism and archaea,[11] although a number of examples have been described in archaea.[15] UBLs are additionally broadly distributed in eukaryotes, however their distribution varies amongst lineages; for instance, ISG15, concerned within the regulation of the immune system, shouldn’t be current in decrease eukaryotes.[1] Different households exhibit diversification in some lineages; a single member of the SUMO household is discovered within the yeast genome, however there are no less than 4 in vertebrate genomes, which present some practical redundancy,[1][2] and there are no less than eight within the genome of the mannequin plant Arabidopsis thaliana.[16]
In people[edit]
The human genome encodes no less than eight households of UBLs, not together with ubiquitin itself, which can be thought-about Kind I UBLs and are identified to covalently modify different proteins: SUMO, NEDD8, ATG8, ATG12, URM1, UFM1, FAT10, and ISG15.[1] One extra protein, often known as FUBI, is encoded as a fusion protein within the FAU gene, and is proteolytically processed to generate a free glycine C-terminus, however has not been experimentally demonstrated to type covalent protein modifications.[1]
In vegetation[edit]
Plant genomes are identified to encode no less than seven households of UBLs along with ubiquitin: SUMO, RUB (the plant homolog of NEDD8), ATG8, ATG12, MUB, UFM1, and HUB1, in addition to plenty of Kind II UBLs.[17] Some UBL households and their related regulatory proteins in vegetation have undergone dramatic enlargement, probably resulting from each complete genome duplication and different types of gene duplication; the ubiquitin, SUMO, ATG8, and MUB households have been estimated to account for nearly 90% of vegetation’ UBL genes.[18] Proteins related to ubiquitin and SUMO signaling are extremely enriched within the genomes of embryophytes.[15]
In prokaryotes[edit]
Compared to eukaryotes, prokaryotic proteins with relationships to UBLs are phylogenetically restricted.[19][20] Prokaryotic ubiquitin-like protein (Pup) happens in some actinobacteria and has capabilities carefully analogous to ubiquitin in labeling proteins for proteasomal degradation; nonetheless it’s intrinsically disordered and its evolutionary relationship to UBLs is unclear.[19] A associated protein UBact in some Gram-negative lineages has not too long ago been described.[21] Against this, the protein TtuB in micro organism of the genus Thermus does share the beta-grasp fold with eukaryotic UBLs; it’s reported to have twin capabilities as each a sulfur service protein and a covalently conjugated protein modification.[19] In archaea, the small archaeal modifier proteins (SAMPs) share the beta-grasp fold and have been proven to play a ubiquitin-like function in protein degradation.[19][20] Not too long ago, a seemingly full set of genes comparable to a eukaryote-like ubiquitin pathway was recognized in an uncultured archaeon in 2011,[22][23][24] and no less than three lineages of archaea – Euryarchaeota, Crenarchaeota, and Aigarchaeota – are believed to own such techniques.[15][25][26] As well as, some pathogenic micro organism have advanced proteins that mimic these in eukaryotic UBL pathways and work together with UBLs within the host cell, interfering with their signaling perform.[27][28]
Regulation[edit] – “like protein”
Regulation of UBLs which can be able to covalent conjugation in eukaryotes is elaborate however usually parallel for every member of the household, greatest characterised for ubiquitin itself. The method of ubiquitination is a tightly regulated three-step sequence: activation, carried out by ubiquitin-activating enzymes (E1); conjugation, carried out by ubiquitin-conjugating enzymes (E2); and ligation, carried out by ubiquitin ligases (E3). The results of this course of is the formation of a covalent bond between the C-terminus of ubiquitin and a residue (usually a lysine) on the goal protein. Many UBL households have the same three-step course of catalyzed by a definite set of enzymes particular to that household.[1][29][30] Deubiquitination or deconjugation – that’s, elimination of ubiquitin from a protein substrate – is carried out by deubiquitinating enzymes (DUBs); UBLs may also be degraded by means of the motion of ubiquitin-specific proteases (ULPs).[31] The vary of UBLs on which these enzymes can act is variable and could be tough to foretell. Some UBLs, resembling SUMO and NEDD8, have family-specific DUBs and ULPs.[32]
Ubiquitin is able to forming polymeric chains, with extra ubiquitin molecules covalently connected to the primary, which in flip is connected to its protein substrate. These chains could also be linear or branched, and totally different regulatory indicators could also be despatched by variations within the size and branching of the ubiquitin chain.[31] Though not all UBL households are identified to type chains, SUMO, NEDD8, and URM1 chains have all been experimentally detected.[1] Moreover, ubiquitin can itself be modified by UBLs, identified to happen with SUMO and NEDD8.[31][33] The very best-characterized intersections between distinct UBL households contain ubiquitin and SUMO.[34][35]
Mobile capabilities[edit]
UBLs as a category are concerned in a really massive number of mobile processes. Moreover, particular person UBL households fluctuate within the scope of their actions and the range of the proteins to which they’re conjugated.[1] The very best identified perform of ubiquitin is figuring out proteins to be degraded by the proteasome, however ubiquitination can play a task in different processes resembling endocytosis and different types of protein trafficking, transcription and transcription issue regulation, cell signaling, histone modification, and DNA restore.[11][12][36] Most different UBLs have related roles in regulating mobile processes, normally with a extra restricted identified vary than that of ubiquitin itself. SUMO proteins have the widest number of mobile protein targets after ubiquitin[1] and are concerned in processes together with transcription, DNA restore, and the mobile stress response.[33] NEDD8 is greatest identified for its function in regulating cullin proteins, which in flip regulate ubiquitin-mediated protein degradation,[2] although it probably additionally has different capabilities.[37] Two UBLs, ATG8 and ATG12, are concerned within the technique of autophagy;[38] each are uncommon in that ATG12 has solely two identified protein substrates and ATG8 is conjugated to not a protein however to a phospholipid, phosphatidylethanolamine.[1]
Evolution[edit]
The evolution of UBLs and their related suites of regulatory proteins has been of curiosity since shortly after they had been acknowledged as a household.[39] Phylogenetic research of the beta-grasp protein fold superfamily counsel that eukaryotic UBLs are monophyletic, indicating a shared evolutionary origin.[13] UBL regulatory techniques – together with UBLs themselves and the cascade of enzymes that work together with them – are believed to share a typical evolutionary origin with prokaryotic biosynthesis pathways for the cofactors thiamine and molybdopterin; the bacterial sulfur switch proteins ThiS and MoaD from these pathways share the beta-grasp fold with UBLs, whereas sequence similarity and a typical catalytic mechanism hyperlink pathway members ThiF and MoeB to ubiquitin-activating enzymes.[13][17][11] Apparently, the eukaryotic protein URM1 capabilities as each a UBL and a sulfur-carrier protein, and has been described as a molecular fossil establishing this evolutionary hyperlink.[11][40]
Comparative genomics surveys of UBL households and associated proteins counsel that UBL signaling was already well-developed within the final eukaryotic widespread ancestor and finally originates from ancestral archaea,[15] a concept supported by the statement that some archaeal genomes possess the required genes for a completely functioning ubiquitination pathway.[25][18] Two totally different diversification occasions throughout the UBL household have been recognized in eukaryotic lineages, comparable to the origin of multicellularity in each animal and plant lineages.[15]
“like protein”