UBA protein domain

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UBA
2jy6 ub with uba ile44 blue.png
The NMR structure of a UBA domain from the protein ubiquilin-1 (top, cyan) bound to ubiquitin (bottom, orange), illustrating the three-helix bundle structure of the UBA domain. Isoleucine 44, the center of a hydrophobic patch on the ubiquitin surface that interacts with a number of ubiquitin-binding domains, is highlighted in blue. Rendered from PDB: 2JY6 ​. [1]
Identifiers
SymbolUBA
Pfam PF00627
Pfam clan CL0214
InterPro IPR015940
PROSITE PDOC50030
SCOP2 1efu / SCOPe / SUPFAM
CDD cd00194
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

Ubiquitin-associated (UBA) domains are protein domains that non-covalently interact with ubiquitin through protein-protein interactions. Ubiquitin is a small protein that is covalently linked to other proteins as part of intracellular signaling pathways, often as a signal for protein degradation. UBA domains are among the most common ubiquitin-binding domains. [2] [3]

Contents

Function

Proteins containing UBA domains are involved in a variety of additional cell processes, such as nucleotide excision repair (NER), spindle pole body duplication, and cell growth. [4]

Protein degradation via the ubiquitin proteasome system (UPS) allows the cell to selectively negatively regulate intracellular proteins. Protein degradation helps to maintain protein quality control, signalling, and cell cycle progression. [5] [6] UBA has been proposed to limit ubiquitin chain elongation and to target polyubiquitinated proteins to the 26S proteasome for degradation. [7] They have been identified in modular proteins involved in protein trafficking, DNA repair, proteasomal degradation, and cell cycle regulation.

Structure

UBA domains have a common sequence motif of approximately 45 amino acid residues. [8] They fold into three-helix bundle structures. [2]

Examples

The structure of the prokaryotic elongation factor EF-Ts bound to EF-Tu. Rendered from PDB: 1EFU . PDB 1efu EBI.jpg
The structure of the prokaryotic elongation factor EF-Ts bound to EF-Tu. Rendered from PDB: 1EFU ​.

The human homologue of yeast Rad23A is one example of a nucleotide excision-repair protein that contains both an internal and a C-terminal UBA domain. The solution structure of human Rad23A UBA(2) showed that the domain forms a compact three-helix bundle. [10]

Comparison of the structures of UBA(1) and UBA(2) reveals that both form very similar folds and have a conserved large hydrophobic surface patch which may be a common protein-interacting surface present in diverse UBA domains. Evidence that ubiquitin binds to UBA domains leads to the prediction that the hydrophobic surface patch of UBA domains interacts with the hydrophobic surface on the five-stranded beta-sheet of ubiquitin. [11]

This domain is similar in sequence to the N-terminal domain of translation elongation factor EF1B (or EF-Ts) from bacteria, mitochondria and chloroplasts. [9]

Related Research Articles

<span class="mw-page-title-main">Proteasome</span> Protein complexes which degrade unnecessary or damaged proteins by proteolysis

Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases.

<span class="mw-page-title-main">Ubiquitin</span> Regulatory protein found in most eukaryotic tissues

Ubiquitin is a small regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ubiquitously. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Four genes in the human genome code for ubiquitin: UBB, UBC, UBA52 and RPS27A.

<span class="mw-page-title-main">Ornithine decarboxylase</span>

The enzyme ornithine decarboxylase catalyzes the decarboxylation of ornithine to form putrescine. This reaction is the committed step in polyamine synthesis. In humans, this protein has 461 amino acids and forms a homodimer.

<span class="mw-page-title-main">Ubiquitin ligase</span> Protein

A ubiquitin ligase is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin from the E2 to the protein substrate. In simple and more general terms, the ligase enables movement of ubiquitin from a ubiquitin carrier to another thing by some mechanism. The ubiquitin, once it reaches its destination, ends up being attached by an isopeptide bond to a lysine residue, which is part of the target protein. E3 ligases interact with both the target protein and the E2 enzyme, and so impart substrate specificity to the E2. Commonly, E3s polyubiquitinate their substrate with Lys48-linked chains of ubiquitin, targeting the substrate for destruction by the proteasome. However, many other types of linkages are possible and alter a protein's activity, interactions, or localization. Ubiquitination by E3 ligases regulates diverse areas such as cell trafficking, DNA repair, and signaling and is of profound importance in cell biology. E3 ligases are also key players in cell cycle control, mediating the degradation of cyclins, as well as cyclin dependent kinase inhibitor proteins. The human genome encodes over 600 putative E3 ligases, allowing for tremendous diversity in substrates.

<span class="mw-page-title-main">UBA1</span> Protein-coding gene in the species Homo sapiens

Ubiquitin-like modifier activating enzyme 1 (UBA1) is an enzyme which in humans is encoded by the UBA1 gene. UBA1 participates in ubiquitination and the NEDD8 pathway for protein folding and degradation, among many other biological processes. This protein has been linked to X-linked spinal muscular atrophy type 2, neurodegenerative diseases, and cancers.

<span class="mw-page-title-main">Endoplasmic-reticulum-associated protein degradation</span>

Endoplasmic-reticulum-associated protein degradation (ERAD) designates a cellular pathway which targets misfolded proteins of the endoplasmic reticulum for ubiquitination and subsequent degradation by a protein-degrading complex, called the proteasome.

<span class="mw-page-title-main">ADP-ribosylation</span> Addition of one or more ADP-ribose moieties to a protein.

ADP-ribosylation is the addition of one or more ADP-ribose moieties to a protein. It is a reversible post-translational modification that is involved in many cellular processes, including cell signaling, DNA repair, gene regulation and apoptosis. Improper ADP-ribosylation has been implicated in some forms of cancer. It is also the basis for the toxicity of bacterial compounds such as cholera toxin, diphtheria toxin, and others.

<span class="mw-page-title-main">PSMA3</span> Protein found in humans

Proteasome subunit alpha type-3 also known as macropain subunit C8 and proteasome component C8 is a protein that in humans is encoded by the PSMA3 gene. This protein is one of the 17 essential subunits that contributes to the complete assembly of 20S proteasome complex.

<span class="mw-page-title-main">RAD23A</span> Protein-coding gene in the species Homo sapiens

UV excision repair protein RAD23 homolog A is a protein that in humans is encoded by the RAD23A gene.

<span class="mw-page-title-main">RAD23B</span> Protein-coding gene in the species Homo sapiens

UV excision repair protein RAD23 homolog B is a protein that in humans is encoded by the RAD23B gene.

<span class="mw-page-title-main">Valosin-containing protein</span> Protein-coding gene in the species Homo sapiens

Valosin-containing protein (VCP) or transitional endoplasmic reticulum ATPase also known as p97 in mammals and CDC48 in S. cerevisiae, is an enzyme that in humans is encoded by the VCP gene. The TER ATPase is an ATPase enzyme present in all eukaryotes and archaebacteria. Its main function is to segregate protein molecules from large cellular structures such as protein assemblies, organelle membranes and chromatin, and thus facilitate the degradation of released polypeptides by the multi-subunit protease proteasome.

<span class="mw-page-title-main">PSMD4</span> Enzyme found in humans

26S proteasome non-ATPase regulatory subunit 4, also as known as 26S Proteasome Regulatory Subunit Rpn10, is an enzyme that in humans is encoded by the PSMD4 gene. This protein is one of the 19 essential subunits that contributes to the complete assembly of 19S proteasome complex.

<span class="mw-page-title-main">PSMA6</span> Protein found in humans

Proteasome subunit alpha type-6 is a protein that in humans is encoded by the PSMA6 gene. This protein is one of the 17 essential subunits that contributes to the complete assembly of 20S proteasome complex.

<span class="mw-page-title-main">PSMD2</span> Enzyme found in humans

26S proteasome non-ATPase regulatory subunit 2, also as known as 26S Proteasome Regulatory Subunit Rpn1, is an enzyme that in humans is encoded by the PSMD2 gene.

<span class="mw-page-title-main">NFE2L1</span> Protein-coding gene in the species Homo sapiens

Nuclear factor erythroid 2-related factor 1 (Nrf1) also known as nuclear factor erythroid-2-like 1 (NFE2L1) is a protein that in humans is encoded by the NFE2L1 gene. Since NFE2L1 is referred to as Nrf1, it is often confused with nuclear respiratory factor 1 (Nrf1).

<span class="mw-page-title-main">ADRM1</span> Protein-coding gene in the species Homo sapiens

Proteasomal ubiquitin receptor ADRM1 is a protein that in humans is encoded by the ADRM1 gene. Recent evidences on proteasome complex structure confirmed that the protein encoded by gene ADRM1, also known in yeast as 26S Proteasome regulatory subunit Rpn13, is a subunit of 19S proteasome complex.

<span class="mw-page-title-main">Prokaryotic ubiquitin-like protein</span>

Prokaryotic ubiquitin-like protein (Pup) is a functional analog of ubiquitin found in the prokaryote Mycobacterium tuberculosis. Like ubiquitin, Pup serves to direct proteins to the proteasome for degradation in the Pup-proteasome system (PPS). However, the enzymology of ubiquitylation and pupylation is different, owing to their distinct evolutionary origins. In contrast to the three-step reaction of ubiquitylation, pupylation requires only two steps, and thus only two enzymes are involved in pupylation. The enzymes involved in pupylation are descended from glutamine synthetase.

<span class="mw-page-title-main">Ubiquitin-interacting motif</span>

In molecular biology, the Ubiquitin-Interacting Motif (UIM), or 'LALAL-motif', is a sequence motif of about 20 amino acid residues, which was first described in the 26S proteasome subunit PSD4/RPN-10 that is known to recognise ubiquitin. In addition, the UIM is found, often in tandem or triplet arrays, in a variety of proteins either involved in ubiquitination and ubiquitin metabolism, or known to interact with ubiquitin-like modifiers. Among the UIM proteins are two different subgroups of the UBP family of deubiquitinating enzymes, one F-box protein, one family of HECT-containing ubiquitin-ligases (E3s) from plants, and several proteins containing ubiquitin-associated UBA and/or UBX domains. In most of these proteins, the UIM occurs in multiple copies and in association with other domains such as UBA, UBX, ENTH domain, EH, VHS, SH3 domain, HECT, VWFA, EF-hand calcium-binding, WD-40, F-box, LIM, protein kinase, ankyrin, PX, phosphatidylinositol 3- and 4-kinase, C2 domain, OTU, DnaJ domain, RING-finger or FYVE-finger. UIMs have been shown to bind ubiquitin and to serve as a specific targeting signal important for monoubiquitination. Thus, UIMs may have several functions in ubiquitin metabolism each of which may require different numbers of UIMs.

<span class="mw-page-title-main">Ubiquitin-binding domain</span> Type of protein domain

Ubiquitin-binding domains (UBDs) are protein domains that recognise and bind non-covalently to ubiquitin through protein-protein interactions. As of 2019, a total of 29 types of UBDs had been identified in the human proteome. Most UBDs bind to ubiquitin only weakly, with binding affinities in the low to mid μM range. Proteins containing UBDs are known as ubiquitin-binding proteins or sometimes as "ubiquitin receptors".

UBXD8 is a protein in the Ubiquitin regulatory X (UBX) domain-containing protein family. The UBX domain contains many eukaryotic proteins that have similarities in amino acid sequence to the tiny protein modifier ubiquitin. UBXD8 engages in a molecular interaction with p97, a protein that is essential for the degradation of membrane proteins associated with the endoplasmic reticulum (ER) through the proteasome. Ubxd8 possesses a UBA domain, alongside the UBX domain, that could interact with polyubiquitin chains. Additionally, it possesses a UAS domain of undetermined function, and this protein is used as a protein sensor that detects long chain unsaturated fatty acids (FAs), having a vital function in regulating the balance of Fatty Acids within cells to maintain cellular homeostasis.

References

  1. ↑ Zhang D, Raasi S, Fushman D (March 2008). "Affinity makes the difference: nonselective interaction of the UBA domain of Ubiquilin-1 with monomeric ubiquitin and polyubiquitin chains". Journal of Molecular Biology. 377 (1): 162–80. doi:10.1016/j.jmb.2007.12.029. PMC   2323583 . PMID   18241885.
  2. 1 2 Dikic I, Wakatsuki S, Walters KJ (October 2009). "Ubiquitin-binding domains - from structures to functions". Nature Reviews. Molecular Cell Biology. 10 (10): 659–71. doi:10.1038/nrm2767. PMC   7359374 . PMID   19773779.
  3. ↑ Husnjak K, Dikic I (7 July 2012). "Ubiquitin-binding proteins: decoders of ubiquitin-mediated cellular functions". Annual Review of Biochemistry. 81 (1): 291–322. doi:10.1146/annurev-biochem-051810-094654. PMID   22482907.
  4. ↑ Su V, Lau AF (September 2009). "Ubiquitin-like and ubiquitin-associated domain proteins: significance in proteasomal degradation". Cellular and Molecular Life Sciences. 66 (17): 2819–33. doi:10.1007/s00018-009-0048-9. PMC   2725189 . PMID   19468686.
  5. ↑ Gomez TA, Kolawa N, Gee M, Sweredoski MJ, Deshaies RJ (May 2011). "Identification of a functional docking site in the Rpn1 LRR domain for the UBA-UBL domain protein Ddi1". BMC Biology. 9: 33. doi: 10.1186/1741-7007-9-33 . PMC   3126750 . PMID   21627799.
  6. ↑ Tse MK, Hui SK, Yang Y, Yin ST, Hu HY, Zou B, et al. (2011). "Structural analysis of the UBA domain of X-linked inhibitor of apoptosis protein reveals different surfaces for ubiquitin-binding and self-association". PLOS ONE. 6 (12): e28511. Bibcode:2011PLoSO...628511T. doi: 10.1371/journal.pone.0028511 . PMC   3240630 . PMID   22194841.
  7. ↑ Li J, Chu H, Zhang Y, Mou T, Wu C, Zhang Q, Xu J (2012). "The rice HGW gene encodes a ubiquitin-associated (UBA) domain protein that regulates heading date and grain weight". PLOS ONE. 7 (3): e34231. Bibcode:2012PLoSO...734231L. doi: 10.1371/journal.pone.0034231 . PMC   3311617 . PMID   22457828.
  8. ↑ Hofmann K, Bucher P (May 1996). "The UBA domain: a sequence motif present in multiple enzyme classes of the ubiquitination pathway". Trends in Biochemical Sciences. 21 (5): 172–3. doi:10.1016/S0968-0004(96)30015-7. PMID   8871400.
  9. 1 2 Kawashima, Takemasa; Berthet-Colominas, Carmen; Wulff, Michael; Cusack, Stephen; Leberman, Reuben (8 February 1996). "The structure of the Escherichia coli EF-Tu· EF-Ts complex at 2.5 Å resolution". Nature. 379 (6565): 511–518. Bibcode:1996Natur.379..511K. doi:10.1038/379511a0. PMID   8596629. S2CID   4273375.
  10. ↑ Dieckmann T, Withers-Ward ES, Jarosinski MA, Liu CF, Chen IS, Feigon J (December 1998). "Structure of a human DNA repair protein UBA domain that interacts with HIV-1 Vpr". Nature Structural Biology. 5 (12): 1042–7. doi:10.1038/4220. PMID   9846873. S2CID   30478711.
  11. ↑ Mueller TD, Feigon J (June 2002). "Solution structures of UBA domains reveal a conserved hydrophobic surface for protein-protein interactions". Journal of Molecular Biology. 319 (5): 1243–55. doi:10.1016/S0022-2836(02)00302-9. PMID   12079361.
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