Interaction with the Assembly Chaperone Ump1 Promotes Incorporation of the β7 Subunit into Half-Proteasome Precursor Complexes Driving Their Dimerization

Zimmermann, Jessica; Ramos, Paula C.; Dohmen, R. Jürgen

doi:10.3390/biom12020253

Cited by 6 publications

(7 citation statements)

References 39 publications

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“…The most consistent and sizable truncations occur within β5 and β7 propeptides (Fig. 6c ), which recruit β6 and promote proteasome dimerization via interactions with Ump1, respectively 61 , 62 . Contrary to the tendency towards reduction, many microsporidians have expanded their β6 propeptides by >70 amino acids.…”

Section: Resultsmentioning

confidence: 94%

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Structure of the reduced microsporidian proteasome bound by PI31-like peptides in dormant spores

et al. 2022

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Proteasomes play an essential role in the life cycle of intracellular pathogens with extracellular stages by ensuring proteostasis in environments with limited resources. In microsporidia, divergent parasites with extraordinarily streamlined genomes, the proteasome complexity and structure are unknown, which limits our understanding of how these unique pathogens adapt and compact essential eukaryotic complexes. We present cryo-electron microscopy structures of the microsporidian 20S and 26S proteasome isolated from dormant or germinated Vairimorpha necatrix spores. The discovery of PI31-like peptides, known to inhibit proteasome activity, bound simultaneously to all six active sites within the central cavity of the dormant spore proteasome, suggests reduced activity in the environmental stage. In contrast, the absence of the PI31-like peptides and the existence of 26S particles post-germination in the presence of ATP indicates that proteasomes are reactivated in nutrient-rich conditions. Structural and phylogenetic analyses reveal that microsporidian proteasomes have undergone extensive reductive evolution, lost at least two regulatory proteins, and compacted nearly every subunit. The highly derived structure of the microsporidian proteasome, and the minimized version of PI31 presented here, reinforce the feasibility of the development of specific inhibitors and provide insight into the unique evolution and biology of these medically and economically important pathogens.

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Section: Resultsmentioning

confidence: 94%

“…The propeptides of the β subunits are also frequently modified. These segments are integral to the assembly process, where they protect catalytic residues and recruit other subunits and assembly factors 61 , 62 . The most consistent and sizable truncations occur within β5 and β7 propeptides (Fig.…”

Section: Resultsmentioning

confidence: 99%

Structure of the reduced microsporidian proteasome bound by PI31-like peptides in dormant spores

et al. 2022

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“…The most consistent and sizable truncations occur within β5 and β7 propeptides ( Fig. 6c ), which recruit β6 and promote proteasome dimerization via interactions with Ump1, respectively 55,56 . Contrary to the tendency to extreme reduction, many microsporidians have expanded their β6 propeptides by more than 70 amino acids.…”

Section: Resultsmentioning

confidence: 94%

“…The propeptides of the β subunits are also frequently modified. These segments are integral to the assembly process, where they protect catalytic residues and recruit other subunits and assembly factors 55,56 . The most consistent and sizable truncations occur within β5 and β7 propeptides ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Reductive evolution in the structure of the microsporidian proteasome

Jespersen

Ehrenbolger

Winiger

et al. 2022

Preprint

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Proteasomes play an essential role in the life cycle of intracellular pathogens with extracellular stages by ensuring proteostasis in environments with limited resources. In microsporidia, divergent parasites with extraordinarily streamlined genomes, the proteasome complexity and structure are unknown, which limits our understanding of how these unique pathogens adapt and compact essential eukaryotic complexes. We present cryo-electron microscopy structures of the microsporidian 20S and 26S proteasome isolated from dormant or germinated Vairimorpha necatrix spores. The presence of distinct densities within the central cavity of the dormant spore proteasome suggests reduced activity in the environmental stage. In contrast, the absence of these densities and the existence of 26S particles post-germination indicates rapid reactivation of proteasomes after host infection. Structual and phylogenetic analyses reveal that microsporidian proteasomes have undergone extreme reductive evolution, lost three regulatory proteins, and compacted nearly every subunit. The highly derived microsporidian proteasome structure presented here reinforces the feasibility of the development of specific inhibitors and provides insight into the unique evolution and biology of these medically and economically important pathogens.

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“…CP formation by dimerization of two such complexes is triggered by incorporation of β7 subunits, the C-terminal extensions of which reach out to the respective other halves to stabilize the newly formed 20S particle [17,21]. Recently, we reported that β7 recruitment is promoted by an N-terminal domain of Ump1 that interacts with the β7 pro-peptide [22]. Upon maturation of the active sites by autocatalytic processing, the assembly chaperones Ump1 is degraded, and Pba1-Pba2 is released [9,19].…”

Section: Introductionmentioning

confidence: 99%

Hsp70 and Hsp110 Chaperones Promote Early Steps of Proteasome Assembly

et al. 2022

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Whereas assembly of the 20S proteasome core particle (CP) in prokaryotes apparently occurs spontaneously, the efficiency of this process in eukaryotes relies on the dedicated assembly chaperones Ump1, Pba1-Pba2, and Pba3-Pba4. For mammals, it was reported that CP assembly initiates with formation of a complete α-ring that functions as a template for β subunit incorporation. By contrast, we were not able to detect a ring composed only of a complete set of α subunits in S. cerevisiae. Instead, we found that the CP subunits α1, α2, and α4 each form independent small complexes. Purification of such complexes containing α4 revealed the presence of chaperones of the Hsp70/Ssa and Hsp110/Sse families. Consistently, certain small complexes containing α1, α2, and α4 were not formed in strains lacking these chaperones. Deletion of the SSE1 gene in combination with deletions of PRE9 (α3), PBA3, or UMP1 genes resulted in severe synthetic growth defects, high levels of ubiquitin-conjugates, and an accumulation of distinct small complexes with α subunits. Our study shows that Hsp70 and Hsp110 chaperones cooperate to promote the folding of individual α subunits and/or their assembly with other CP subunits, Ump1, and Pba1-Pba4 in subsequent steps.

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Interaction with the Assembly Chaperone Ump1 Promotes Incorporation of the β7 Subunit into Half-Proteasome Precursor Complexes Driving Their Dimerization

Cited by 6 publications

References 39 publications

Structure of the reduced microsporidian proteasome bound by PI31-like peptides in dormant spores

Structure of the reduced microsporidian proteasome bound by PI31-like peptides in dormant spores

Reductive evolution in the structure of the microsporidian proteasome

Hsp70 and Hsp110 Chaperones Promote Early Steps of Proteasome Assembly

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