Biology:Ubiquitin-like protein

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Short description: Family of small proteins
Ubiquitin family
1ubq 1ndd superposition.png
Superposition of the structures of ubiquitin (PDB: 1UBQ​, green) and NEDD8 (PDB: 1NDD​, magenta)
Identifiers
SymbolUbiquitin
PfamPF00240
InterProIPR029071
SMARTSM00213

Ubiquitin-like proteins (UBLs) are a family of small proteins involved in post-translational modification of other proteins in a cell, usually with a regulatory function. The UBL protein family derives its name from the first member of the class to be discovered, ubiquitin (Ub), best known for its role in regulating protein degradation through covalent modification of other proteins. Following the discovery of ubiquitin, many additional evolutionarily related members of the group were described, involving parallel regulatory processes and similar chemistry. UBLs are involved in a widely varying array of cellular functions including autophagy, protein trafficking, inflammation and immune responses, transcription, DNA repair, RNA splicing, and cellular differentiation.[1][2][3]

Discovery

Ubiquitin itself was first discovered in the 1970s and originally named "ubiquitous immunopoietic polypeptide".[4] Subsequently, other proteins with sequence similarity to ubiquitin were occasionally reported in the literature, but the first shown to share the key feature of covalent protein modification was ISG15, discovered in 1987.[5] A succession of reports in the mid 1990s is recognized as a turning point in the field,[6] with the discovery of SUMO (small ubiquitin-like modifier, also known as Sentrin or SENP1) reported around the same time by a variety of investigators in 1996,[7] NEDD8 in 1997,[8] and Apg12 in 1998.[9] A systematic survey has since identified over 10,000 distinct genes for ubiquitin or ubiquitin-like proteins represented in eukaryotic genomes.[10]

Structure and classification

Members of the UBL family are small, non-enzymatic proteins that share a common structure exemplified by ubiquitin, which has 76 amino acid residues arranged 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 widely distributed in other proteins of both eukaryotic and prokaryotic origin.[13] Collectively, ubiquitin and ubiquitin-like proteins are sometimes referred to as "ubiquitons".[3]

UBLs can be divided into two categories depending on their ability to be covalently conjugated to other molecules. UBLs that are capable of conjugation (sometimes known as Type I) have a characteristic sequence motif consisting of one to two glycine residues at the C-terminus, through which covalent conjugation occurs. Typically, UBLs are expressed as inactive precursors and must be activated by proteolysis of the C-terminus to expose the active glycine.[1][12] Almost all such UBLs are ultimately linked to another protein, but there is at least one exception; ATG8 is linked to phosphatidylethanolamine.[1] UBLs that do not exhibit covalent conjugation (Type II) often occur as protein domains genetically fused to other domains in a single larger polypeptide chain, and may be proteolytically processed to release the UBL domain[1] or may function as protein-protein interaction domains.[11] UBL domains of larger proteins are sometimes known as UBX domains.[14]

Distribution

Ubiquitin is, as its name suggests, ubiquitous in eukaryotes; it is traditionally considered to be absent in bacteria and archaea,[11] though a few examples have been described in archaea.[15] UBLs are also widely distributed in eukaryotes, but their distribution varies among lineages; for example, ISG15, involved in the regulation of the immune system, is not present in lower eukaryotes.[1] Other families exhibit diversification in some lineages; a single member of the SUMO family is found in the yeast genome, but there are at least four in vertebrate genomes, which show some functional redundancy,[1][2] and there are at least eight in the genome of the model plant Arabidopsis thaliana.[16]

In humans

The human genome encodes at least eight families of UBLs, not including ubiquitin itself, that are considered Type I UBLs and are known to covalently modify other proteins: SUMO, NEDD8, ATG8, ATG12, URM1, UFM1, FAT10, and ISG15.[1] One additional protein, known as FUBI, is encoded as a fusion protein in the FAU gene, and is proteolytically processed to generate a free glycine C-terminus, but has not been experimentally demonstrated to form covalent protein modifications.[1]

In plants

Plant genomes are known to encode at least seven families of UBLs in addition to ubiquitin: SUMO, RUB (the plant homolog of NEDD8), ATG8, ATG12, MUB, UFM1, and HUB1, as well as a number of Type II UBLs.[17] Some UBL families and their associated regulatory proteins in plants have undergone dramatic expansion, likely due to both whole genome duplication and other forms of gene duplication; the ubiquitin, SUMO, ATG8, and MUB families have been estimated to account for almost 90% of plants' UBL genes.[18] Proteins associated with ubiquitin and SUMO signaling are highly enriched in the genomes of embryophytes.[15]

In prokaryotes

Superposition of the structures of ubiquitin (PDB: 1UBQ​, green) and SAMP1 (PDB: 2L52​, orange)

In comparison to eukaryotes, prokaryotic proteins with relationships to UBLs are phylogenetically restricted.[19][20] Prokaryotic ubiquitin-like protein (Pup) occurs in some actinobacteria and has functions closely analogous to ubiquitin in labeling proteins for proteasomal degradation; however it is intrinsically disordered and its evolutionary relationship to UBLs is unclear.[19] A related protein UBact in some Gram-negative lineages has recently been described.[21] By contrast, the protein TtuB in bacteria of the genus Thermus does share the beta-grasp fold with eukaryotic UBLs; it is reported to have dual functions as both a sulfur carrier protein and a covalently conjugated protein modification.[19] In archaea, the small archaeal modifier proteins (SAMPs) share the beta-grasp fold and have been shown to play a ubiquitin-like role in protein degradation.[19][20] Recently, a seemingly complete set of genes corresponding to a eukaryote-like ubiquitin pathway was identified in an uncultured archaeon in 2011,[22][23][24] and at least three lineages of archaea—"Euryarchaeota", Thermoproteota (formerly Crenarchaeota), and "Aigarchaeota"—are believed to possess such systems.[15][25][26] In addition, some pathogenic bacteria have evolved proteins that mimic those in eukaryotic UBL pathways and interact with UBLs in the host cell, interfering with their signaling function.[27][28]

Regulation

Crystal structure of the complex between the ubiquitin-like protein SUMO-1 (dark blue) and its activating enzyme (E1), a heterodimer between SAE1 and SAE2 (light blue, pink). The C-terminus of the SUMO protein is located near the ATP site (yellow). From PDB: 1Y8R​.

Regulation of UBLs that are capable of covalent conjugation in eukaryotes is elaborate but typically parallel for each member of the family, best characterized for ubiquitin itself. The process of ubiquitination is a tightly regulated three-step sequence: activation, performed by ubiquitin-activating enzymes (E1); conjugation, performed by ubiquitin-conjugating enzymes (E2); and ligation, performed by ubiquitin ligases (E3). The result of this process is the formation of a covalent bond between the C-terminus of ubiquitin and a residue (typically a lysine) on the target protein. Many UBL families have a similar three-step process catalyzed by a distinct set of enzymes specific to that family.[1][29][30] Deubiquitination or deconjugation - that is, removal of ubiquitin from a protein substrate - is performed by deubiquitinating enzymes (DUBs); UBLs can also be degraded through the action of ubiquitin-specific proteases (ULPs).[31] The range of UBLs on which these enzymes can act is variable and can be difficult to predict. Some UBLs, such as SUMO and NEDD8, have family-specific DUBs and ULPs.[32]

Ubiquitin is capable of forming polymeric chains, with additional ubiquitin molecules covalently attached to the first, which in turn is attached to its protein substrate. These chains may be linear or branched, and different regulatory signals may be sent by differences in the length and branching of the ubiquitin chain.[31] Although not all UBL families are known to form chains, SUMO, NEDD8, and URM1 chains have all been experimentally detected.[1] Additionally, ubiquitin can itself be modified by UBLs, known to occur with SUMO and NEDD8.[31][33] The best-characterized intersections between distinct UBL families involve ubiquitin and SUMO.[34][35]

Cellular functions

UBLs as a class are involved in a very large variety of cellular processes. Furthermore, individual UBL families vary in the scope of their activities and the diversity of the proteins to which they are conjugated.[1] The best known function of ubiquitin is identifying proteins to be degraded by the proteasome, but ubiquitination can play a role in other processes such as endocytosis and other forms of protein trafficking, transcription and transcription factor regulation, cell signaling, histone modification, and DNA repair.[11][12][36] Most other UBLs have similar roles in regulating cellular processes, usually with a more restricted known range than that of ubiquitin itself. SUMO proteins have the widest variety of cellular protein targets after ubiquitin[1] and are involved in processes including transcription, DNA repair, and the cellular stress response.[33] NEDD8 is best known for its role in regulating cullin proteins, which in turn regulate ubiquitin-mediated protein degradation,[2] though it likely also has other functions.[37] Two UBLs, ATG8 and ATG12, are involved in the process of autophagy;[38] both are unusual in that ATG12 has only two known protein substrates and ATG8 is conjugated not to a protein but to a phospholipid, phosphatidylethanolamine.[1]

Evolution

Superposition of the structures of ubiquitin (PDB: 1UBQ​, green) and MoaD (PDB: 1FM0​, light gray)

The evolution of UBLs and their associated suites of regulatory proteins has been of interest since shortly after they were recognized as a family.[39] Phylogenetic studies of the beta-grasp protein fold superfamily suggest that eukaryotic UBLs are monophyletic, indicating a shared evolutionary origin.[13] UBL regulatory systems - including UBLs themselves and the cascade of enzymes that interact with them - are believed to share a common evolutionary origin with prokaryotic biosynthesis pathways for the cofactors thiamine and molybdopterin; the bacterial sulfur transfer proteins ThiS and MoaD from these pathways share the beta-grasp fold with UBLs, while sequence similarity and a common catalytic mechanism link pathway members ThiF and MoeB to ubiquitin-activating enzymes.[13][17][11] Interestingly, the eukaryotic protein URM1 functions as both a UBL and a sulfur-carrier protein, and has been described as a molecular fossil establishing this evolutionary link.[11][40]

Comparative genomics surveys of UBL families and related proteins suggest that UBL signaling was already well-developed in the last eukaryotic common ancestor and ultimately originates from ancestral archaea,[15] a theory supported by the observation that some archaeal genomes possess the necessary genes for a fully functioning ubiquitination pathway.[25][18] Two different diversification events within the UBL family have been identified in eukaryotic lineages, corresponding to the origin of multicellularity in both animal and plant lineages.[15]

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 "Ubiquitin-like Protein Conjugation: Structures, Chemistry, and Mechanism". Chemical Reviews 118 (3): 889–918. February 2018. doi:10.1021/acs.chemrev.6b00737. PMID 28234446. 
  2. ↑ 2.0 2.1 2.2 "Ubiquitin-like proteins". Annual Review of Biochemistry 81 (1): 323–57. 7 July 2012. doi:10.1146/annurev-biochem-093010-153308. PMID 22404627. 
  3. ↑ 3.0 3.1 "Ubiquitin and ubiquitin-like proteins as multifunctional signals". Nature Reviews. Molecular Cell Biology 6 (8): 599–609. August 2005. doi:10.1038/nrm1700. PMID 16064136. 
  4. ↑ "Isolation of a polypeptide that has lymphocyte-differentiating properties and is probably represented universally in living cells". Proceedings of the National Academy of Sciences of the United States of America 72 (1): 11–5. January 1975. doi:10.1073/pnas.72.1.11. PMID 1078892. Bibcode: 1975PNAS...72...11G. 
  5. ↑ "Interferon induces a 15-kilodalton protein exhibiting marked homology to ubiquitin". The Journal of Biological Chemistry 262 (23): 11315–23. August 1987. doi:10.1016/S0021-9258(18)60961-5. PMID 2440890. http://www.jbc.org/content/262/23/11315.short. 
  6. ↑ "Ubiquitin-like proteins: new wines in new bottles". Gene 248 (1–2): 1–14. May 2000. doi:10.1016/S0378-1119(00)00139-6. PMID 10806345. 
  7. ↑ Saitoh, Hisato; Pu, Robert T.; Dasso, Mary (October 1997). "SUMO-1: wrestling with a new ubiquitin-related modifier". Trends in Biochemical Sciences 22 (10): 374–376. doi:10.1016/S0968-0004(97)01102-X. PMID 9357311. 
  8. ↑ "Characterization of NEDD8, a developmentally down-regulated ubiquitin-like protein". The Journal of Biological Chemistry 272 (45): 28557–62. November 1997. doi:10.1074/jbc.272.45.28557. PMID 9353319. 
  9. ↑ "A protein conjugation system essential for autophagy". Nature 395 (6700): 395–8. September 1998. doi:10.1038/26506. PMID 9759731. Bibcode: 1998Natur.395..395M. 
  10. ↑ "iUUCD 2.0: an update with rich annotations for ubiquitin and ubiquitin-like conjugations". Nucleic Acids Research 46 (D1): D447–D453. January 2018. doi:10.1093/nar/gkx1041. PMID 29106644. 
  11. ↑ 11.0 11.1 11.2 11.3 11.4 11.5 "Origin and function of ubiquitin-like proteins". Nature 458 (7237): 422–9. March 2009. doi:10.1038/nature07958. PMID 19325621. Bibcode: 2009Natur.458..422H. 
  12. ↑ 12.0 12.1 12.2 "Modification of proteins by ubiquitin and ubiquitin-like proteins". Annual Review of Cell and Developmental Biology 22 (1): 159–80. November 2006. doi:10.1146/annurev.cellbio.22.010605.093503. PMID 16753028. 
  13. ↑ 13.0 13.1 13.2 "Small but versatile: the extraordinary functional and structural diversity of the beta-grasp fold". Biology Direct 2 (1): 18. July 2007. doi:10.1186/1745-6150-2-18. PMID 17605815. 
  14. ↑ "The UBX domain: a widespread ubiquitin-like module". Journal of Molecular Biology 307 (1): 17–24. March 2001. doi:10.1006/jmbi.2000.4462. PMID 11243799. 
  15. ↑ 15.0 15.1 15.2 15.3 15.4 "The eukaryotic ancestor had a complex ubiquitin signaling system of archaeal origin". Molecular Biology and Evolution 32 (3): 726–39. March 2015. doi:10.1093/molbev/msu334. PMID 25525215. 
  16. ↑ "Sumoylation and other ubiquitin-like post-translational modifications in plants". Trends in Cell Biology 20 (4): 223–32. April 2010. doi:10.1016/j.tcb.2010.01.007. PMID 20189809. 
  17. ↑ 17.0 17.1 "The expanding universe of ubiquitin and ubiquitin-like modifiers". Plant Physiology 160 (1): 2–14. September 2012. doi:10.1104/pp.112.200667. PMID 22693286. 
  18. ↑ 18.0 18.1 "Contrasting duplication patterns reflect functional diversities of ubiquitin and ubiquitin-like protein modifiers in plants". The Plant Journal 95 (2): 296–311. July 2018. doi:10.1111/tpj.13951. PMID 29738099. 
  19. ↑ 19.0 19.1 19.2 19.3 "Prokaryotic ubiquitin-like protein modification". Annual Review of Microbiology 68: 155–75. 2014. doi:10.1146/annurev-micro-091313-103447. PMID 24995873. 
  20. ↑ 20.0 20.1 Ganguli, S; Ratna Prabha, C (2017). "Pups, SAMPs, and Prokaryotic Proteasomes". in Chakraborti, S; Dhalla, N. Proteases in physiology and pathology. Springer. ISBN 978-981-10-2512-9. 
  21. ↑ "Identification of UBact, a ubiquitin-like protein, along with other homologous components of a conjugation system and the proteasome in different gram-negative bacteria". Biochemical and Biophysical Research Communications 483 (3): 946–950. February 2017. doi:10.1016/j.bbrc.2017.01.037. PMID 28087277. 
  22. ↑ "Insights into the evolution of Archaea and eukaryotic protein modifier systems revealed by the genome of a novel archaeal group". Nucleic Acids Research 39 (8): 3204–23. April 2011. doi:10.1093/nar/gkq1228. PMID 21169198. 
  23. ↑ "Functional reconstruction of a eukaryotic-like E1/E2/(RING) E3 ubiquitylation cascade from an uncultured archaeon". Nature Communications 8 (1): 1120. October 2017. doi:10.1038/s41467-017-01162-7. PMID 29066714. Bibcode: 2017NatCo...8.1120H. 
  24. ↑ "Rpn11-mediated ubiquitin processing in an ancestral archaeal ubiquitination system". Nature Communications 9 (1): 2696. July 2018. doi:10.1038/s41467-018-05198-1. PMID 30002364. Bibcode: 2018NatCo...9.2696F. 
  25. ↑ 25.0 25.1 "Asgard archaea illuminate the origin of eukaryotic cellular complexity". Nature 541 (7637): 353–358. January 2017. doi:10.1038/nature21031. PMID 28077874. Bibcode: 2017Natur.541..353Z. http://www.escholarship.org/uc/item/0qh5400s. 
  26. ↑ "Genomic inference of the metabolism and evolution of the archaeal phylum Aigarchaeota". Nature Communications 9 (1): 2832. July 2018. doi:10.1038/s41467-018-05284-4. PMID 30026532. Bibcode: 2018NatCo...9.2832H. 
  27. ↑ "Diversity of bacterial manipulation of the host ubiquitin pathways". Cellular Microbiology 17 (1): 26–34. January 2015. doi:10.1111/cmi.12384. PMID 25339545. 
  28. ↑ "Ubiquitin, SUMO, and NEDD8: Key Targets of Bacterial Pathogens". Trends in Cell Biology 28 (11): 926–940. November 2018. doi:10.1016/j.tcb.2018.07.005. PMID 30107971. PMC 7028394. https://hal-pasteur.archives-ouvertes.fr/pasteur-01890548/file/Cossart-Trends%20Cell%20Biol-Manuscript%20preprint.pdf. 
  29. ↑ "Structural and functional insights to ubiquitin-like protein conjugation". Annual Review of Biophysics 43 (1): 357–79. 6 May 2014. doi:10.1146/annurev-biophys-051013-022958. PMID 24773014. 
  30. ↑ "Ubiquitin-like protein activation by E1 enzymes: the apex for downstream signalling pathways". Nature Reviews. Molecular Cell Biology 10 (5): 319–31. May 2009. doi:10.1038/nrm2673. PMID 19352404. 
  31. ↑ 31.0 31.1 31.2 "Mechanisms of Deubiquitinase Specificity and Regulation". Annual Review of Biochemistry 86 (1): 159–192. June 2017. doi:10.1146/annurev-biochem-061516-044916. PMID 28498721. 
  32. ↑ "Substrate specificity of the ubiquitin and Ubl proteases". Cell Research 26 (4): 441–56. April 2016. doi:10.1038/cr.2016.38. PMID 27012468. 
  33. ↑ 33.0 33.1 "Ubiquitin modifications". Cell Research 26 (4): 399–422. April 2016. doi:10.1038/cr.2016.39. PMID 27012465. 
  34. ↑ "SUMO and ubiquitin paths converge". Biochemical Society Transactions 38 (Pt 1): 34–9. February 2010. doi:10.1042/BST0380034. PMID 20074031. 
  35. ↑ "Mechanisms, regulation and consequences of protein SUMOylation". The Biochemical Journal 428 (2): 133–45. May 2010. doi:10.1042/BJ20100158. PMID 20462400. 
  36. ↑ "Proteasome-independent functions of ubiquitin in endocytosis and signaling". Science 315 (5809): 201–5. January 2007. doi:10.1126/science.1127085. PMID 17218518. Bibcode: 2007Sci...315..201M. 
  37. ↑ "Protein neddylation: beyond cullin-RING ligases". Nature Reviews. Molecular Cell Biology 16 (1): 30–44. January 2015. doi:10.1038/nrm3919. PMID 25531226. 
  38. ↑ "Ubiquitin-like proteins and autophagy at a glance". Journal of Cell Science 125 (Pt 10): 2343–8. May 2012. doi:10.1242/jcs.093757. PMID 22736434. 
  39. ↑ "Evolution and function of ubiquitin-like protein-conjugation systems". Nature Cell Biology 2 (8): E153-7. August 2000. doi:10.1038/35019643. PMID 10934491. 
  40. ↑ "The dual role of ubiquitin-like protein Urm1 as a protein modifier and sulfur carrier". Protein & Cell 2 (8): 612–9. August 2011. doi:10.1007/s13238-011-1074-6. PMID 21904977. 



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