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Review
. 2023 Apr 24;13(5):734.
doi: 10.3390/biom13050734.

The Ubiquitin-like Proteins of Saccharomyces cerevisiae

Swarnab Sengupta  1 , Elah Pick  1   2
Affiliations
Review

The Ubiquitin-like Proteins of Saccharomyces cerevisiae

Swarnab Sengupta et al. Biomolecules. .

Abstract

In this review, we present a comprehensive list of the ubiquitin-like modifiers (Ubls) of Saccharomyces cerevisiae, a common model organism used to study fundamental cellular processes that are conserved in complex multicellular organisms, such as humans. Ubls are a family of proteins that share structural relationships with ubiquitin, and which modify target proteins and lipids. These modifiers are processed, activated and conjugated to substrates by cognate enzymatic cascades. The attachment of substrates to Ubls alters the various properties of these substrates, such as function, interaction with the environment or turnover, and accordingly regulate key cellular processes, including DNA damage, cell cycle progression, metabolism, stress response, cellular differentiation, and protein homeostasis. Thus, it is not surprising that Ubls serve as tools to study the underlying mechanism involved in cellular health. We summarize current knowledge on the activity and mechanism of action of the S. cerevisiae Rub1, Smt3, Atg8, Atg12, Urm1 and Hub1 modifiers, all of which are highly conserved in organisms from yeast to humans.

Keywords: Atg12; Atg8; Hub1; NEDDylation; Rub1; S. cerevisiae; SUMOylation; Smt3; Ubls; Urm1; proteostasis; ubiquitin.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Ubiquitin and Ubls in S. cerevisiae. (A) Three-dimensional models of the S. cerevisiae ubiquitin-like modifiers Rub1, Smt3, Atg8, Atg12, Urm1 and Hub1. Protein structures were predicted by alphaFold [35], and superimposed with that of ubiquitin using the UCSF Chimera program (version 1.16). The amino and carboxy termini (N’ and C’) of ubiquitin are presented in black in each of the superimposed models. Note that the long amino terminus of Atg12 is not shown. (B) Phylogenetic tree of H. sapiens (Hs) ubiquitin and the six S. cerevisiae Ubls presented in A. Protein sequences were aligned with Clustal W software, and a neighbor-joining phylogenetic tree of the proteins was inferred from the multiple alignments using MEGA X. (C) Overview of the canonical ubiquitin/ubiquitin-like conjugation cascade. (D) Sequence alignment of S. cerevisiae ubiquitin and the canonical ubiquitin-like modifiers. Sequences were aligned with PROMALS3D server. The alignment indicates the various Lys residues that mediate ubiquitination (green), reveals the difference in charge of the residue used for E1 selection at position 72 (purple) and emphasizes the Gly residue used for conjugation (red).
Figure 2
Figure 2
Rub1 cascade and properties. (A) Schematic depiction of the Rub1 modification cascade and cycle. The Rub1 precursor is processed by the carboxy terminal-acting hydrolase Yuh1. The carboxylic Gly residue of Rub1 forms an adenylate with NAE1, followed by thioester formation. Rub1 is then transthiolized to Ubc12. Finally, Rub1 is transferred to a Lys residue on one of three cullins by two E3 ligases, Hrt1 and Dcn1. Cullin NEDDylation is reversed by the COP9 signalosome, a cullin-specific DeNEDDylase. Notably, CRL components are recycled via the CAND1/Lag2 exchange factor in a mechanism that is beyond the scope of this review. (B) Interactions and functional relationship between CRL components and modifying enzymes, as detailed in the text.
Figure 3
Figure 3
Schematic depiction of the Smt3 cascade. Following Smt3 maturation by Ulp1, the modifier is activated and forms a thioester bond with the heterodimeric Aos1/Uba2 E1 enzyme, followed by transthiolization to the E2 Ubc9. Smt3-Ubc9 interacts with various E3 ligases, resulting in the binding of specific substrates. The Siz1/Siz2 E3 ligase catalyzes the modification of Tgf1 (the large subunit of TFIIF) to avoid the pairing of RNA polymerase II with TFIIF. Siz1 mediates PCNA SUMOylation, and thus contributes to meiosis and genome stability. The E3 Slx5-Slx8 catalyzes Cse4 SUMOylation, which prevents its attraction to euchromatin under normal physiological conditions. The Mms21-Smc5-Smc6 complex facilitates SUMOylation of substrates such as the DNA repair component Yku70.
Figure 4
Figure 4
Atg8/12 cascades and properties. (A) Sequence alignment of ubiquitin (UBI4/UBC) and the carboxyl terminus of Atg12 from H. sapiens and S. cerevisiae. Sequences were aligned using the PROMALS3D server. (B) Schematic depiction of Atg8/Atg12 enzymatic cascades. Atg8 requires the Atg4 protease for its maturation. Subsequently, both Atg8 and Atg12 are activated by the E1-like enzyme Atg7, which first adenylates the C-terminal of each modifier following thioester formation. The next step includes transthiolation of the modifiers from Atg7 to cognate E2 enzymes, namely, Atg10 for Atg12 and Atg3 for Atg8. Next, Atg12 modifies Atg5 that in turn forms a complex with Atg16, all three of which act together as an E3 ligase that catalyzes the Atg8-PE conjugation.
Figure 5
Figure 5
Urm1 cascade and properties. (A) Sequence alignment of ubiquitin (UBI4/UBC) and Urm1 from H. sapiens and S. cerevisiae. Sequences were aligned using the PROMALS3D server. (B) Schematic depiction of the Urm1 cascade. Uba4 is activated via the cascade of sulfur flow starting from cysteine (Cys) through the Nfs and Tum1 proteins. The activated form of Uba4 (Uba4-S-SH) acts as the E1 conjugating enzyme for Urm1 to generate subsequent modifications of Urm1, yielding either to Urm1-COSH or Urm1-CO-Uba4. Urm1-COSH is responsible for tRNA thiolation through Ncs6 and Ncs2 or for URMylation of targets such as Ahp1. The E2 and E3 of this process are still unknown.
Figure 6
Figure 6
Hub1 cascade and properties. (A) Sequence alignment of ubiquitin (UBI4/UBC) and Hub1/UBL5 from H. sapiens and S. cerevisiae. Sequences were aligned using the PROMALS3D server. (B) Schematic depiction of the Hub1 cascade. Hub1 binds to a HIND motif present in the spliceosomal protein Snu66 and promotes the formation of Heh1-S, an alternative splicing of SRC1 pre-mRNA. This variant is dimerized with the canonical mRNA Heh1-L, and together they play an important role in the maintenance of nuclear envelope integrity.
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Research at the Pick lab is funded by the Israel Science Foundation (ISF) grant no. 192/20.

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