The Archaeal Proteasome Is Regulated by a Network of AAA ATPases

Forouzan, Dara; Ammelburg, Moritz; Hobel, Cédric F.V.; Stroh, L.J.; Sessler, Nicole; Martin, Jörg; Lupas, Andrei N.

doi:10.1074/jbc.m112.386458

Cited by 44 publications

(51 citation statements)

References 54 publications

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“…The residues for accommodating the C-terminal tail of HiHslU, Phe 54 , Phe 57 , and Gln 114n are replaced with smaller or shorter residues (i.e. Ile 54 , Met 57 , and Thr 114n , respectively) in TbHslV. This explains why EcHslU and TbHslU1 are not able to activate TbHslV, most probably due to the weak binding.…”

Section: Discussionmentioning

confidence: 95%

“…The HslVU complex in prokaryotes and archaea possesses a simple architecture consisting of a homododecameric HslV and two homohexameric HslUs, but archaeal and eukaryotic proteasomes display a more complicated configuration. In archaea, several proteasomal ATPases, including proteasome-activating nucleotidase and CDC48, constitute a regulatory network (57), and in eukaryotes, heterooligomeric ATPases function within the base of the 19 S regulatory particle. In contrast to prokaryotic and archaeal HslUs, the eukaryotic HslUs from T. brucei and Leishmania donovani possess two HslU homologs, HslU1 and HslU2 (28,29); this suggests several possible configurations of the T. brucei HslVU complex from a structural point of view: 1) two independent TbHslVU1 and TbHslVU2 complexes; 2) TbHslV asymmetrically capped with hexameric rings of TbHslU1 and TbHslU2, and 3) TbHslV complexed with the hetero-oligomeric TbHslU ring consisting of both TbHslU1 and TbHslU2.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Structural and Biochemical Analyses of the Eukaryotic Heat Shock Locus V (HslV) from Trypanosoma brucei

Sung

Lee

Song

2013

Journal of Biological Chemistry

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Background: A eukaryotic HslV (TbHslV) protease and two potential HslU (TbHslU1 and TbHslU2) ATPases have been isolated from Trypanosoma brucei. Results: We determined the crystal structure of TbHslV at 2.4 Å resolution. Only TbHslU2 activated TbHslV protease activity. Conclusion: A key tyrosine residue in TbHslU2 required for activating TbHslV was identified. Significance: This study lays the groundwork for understanding the eukaryotic HslVU system.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Structural and Biochemical Analyses of the Eukaryotic Heat Shock Locus V (HslV) from Trypanosoma brucei

Sung

Lee

Song

2013

Journal of Biological Chemistry

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“…Both D1 and D2 are homologous to the single AAA+ modules of PAN and Rpt1-6 (1,16). Biochemical studies have shown that VAT unfolds globular proteins and interacts directly with the 20S core particle (CP) of the proteasome, leading to enhanced proteolytic activity for both folded and unfolded protein substrates (18)(19)(20)(21). In eukaryotes, the enzymes Cdc48 and p97/VCP, which are homologous to VAT, play essential roles in a large number of cellular functions, including transcriptional and metabolic regulation, cell cycle progression, membrane fusion, apoptosis, and protein degradation (22).…”

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confidence: 99%

Unfolding the mechanism of the AAA+ unfoldase VAT by a combined cryo-EM, solution NMR study

Huang

Ripstein

Augustyniak

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The AAA+ (ATPases associated with a variety of cellular activities) enzymes play critical roles in a variety of homeostatic processes in all kingdoms of life. Valosin-containing protein-like ATPase of Thermoplasma acidophilum (VAT), the archaeal homolog of the ubiquitous AAA+ protein Cdc48/p97, functions in concert with the 20S proteasome by unfolding substrates and passing them on for degradation. Here, we present electron cryomicroscopy (cryo-EM) maps showing that VAT undergoes large conformational rearrangements during its ATP hydrolysis cycle that differ dramatically from the conformational states observed for Cdc48/p97. We validate key features of the model with biochemical and solution methyl-transverse relaxation optimized spectroscopY (TROSY) NMR experiments and suggest a mechanism for coupling the energy of nucleotide hydrolysis to substrate unfolding. These findings illustrate the unique complementarity between cryo-EM and solution NMR for studies of molecular machines, showing that the structural properties of VAT, as well as the population distributions of conformers, are similar in the frozen specimens used for cryo-EM and in the solution phase where NMR spectra are recorded.T he AAA+ enzymes (ATPases associated with a variety of cellular activities) use the energy of ATP hydrolysis to carry out a myriad of different biological functions that are critical to cellular homeostasis. These molecular machines are typically barrel-shaped, containing a narrow channel that serves to traffic substrates through the enzyme (1-4). In the case of the heat shock protein 104 (Hsp104) AAA+ class of chaperone, for example, substrates are dissociated from aggregates via a pulling motion that forces individual polypeptide chains through the central pore of the enzyme (1, 5). The unfolded proteins that emerge subsequently refold spontaneously or are acted on by additional chaperones that aid in their refolding (6). Other AAA+ enzymes act synergistically with proteases, unfolding targeted substrates and passing them directly to the proteases, where they are subsequently degraded (7). In this way, proteins that have become damaged or that are no longer required can be removed before their accumulation disrupts cellular function (8). A variety of different AAA+ unfoldases have been characterized, including Rpt1-6 in the 19S proteasome regulatory particle in eukaryotes (9-11), PAN in archaea (12-14), Mpa/ARC in Actinobacteria (15), ClpA/X (2) and HslU (3) in bacteria, and VAT in the Thermoplasma acidophilum archaebacterium (16)(17)(18)(19)(20).VAT is an ∼500-kDa homohexamer, with each monomer containing two tandem AAA+ domains, referred to as D1 and D2, and an N-terminal domain (NTD) distinct from the NTD of other AAA+ enzymes (16) (Fig. 1A). Both D1 and D2 are homologous to the single AAA+ modules of PAN and Rpt1-6 (1, 16). Biochemical studies have shown that VAT unfolds globular proteins and interacts directly with the 20S core particle (CP) of the proteasome, leading to enhanced proteolytic activity for both folded and ...

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“…2A). Recent studies on the archaeal p97/VCP homolog Cdc48 and the 20S proteasome suggested that direct and functional interactions between Cdc48 and the 20S proteasome can take place in vitro, which align the central cavities of these two ring-shaped complexes, forming a continuous conduit through which substrates are transferred from Cdc48 to the 20S proteasome for degradation Sauer, 2012, 2013;Forouzan et al, 2012). Such interactions, if they exist in eukaryotes, would provide a simple coupling mechanism that links retrotranslocation to degradation.…”

Section: P97/vcp: a Multifaceted Cellular Enzymementioning

confidence: 99%

The Final Moments of Misfolded Proteins en Route to the Proteasome

Zhang

2014

DNA and Cell Biology

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Protein homeostasis in the endoplasmic reticulum (ER) in eukaryotic cells is maintained by a conserved quality control system named ER-associated degradation (ERAD). The ERAD system retains misfolded or unassembled polypeptides in the ER, retrotranslocates them into the cytosol for degradation by the ubiquitin proteasome system. Central to the ERAD process is the AAA + (ATPase associated with various cellular activities), ATPase p97/VCP (also known as Cdc48p in yeast), and the proteasome. p97/VCP couples ATP hydrolysis to the extraction of misfolded proteins from retrotranslocation sites and subsequently targets them for degradation, but how p97/VCP hands substrate off to the proteasome is unclear. Recent studies suggest that p97/VCP may either directly translocate polypeptides into the proteolytic compartment of the 20S subcomplex, or use a set of shuttling factors to deliver retrotranslocated polypeptides to the proteasome.

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The Archaeal Proteasome Is Regulated by a Network of AAA ATPases

Cited by 44 publications

References 54 publications

Structural and Biochemical Analyses of the Eukaryotic Heat Shock Locus V (HslV) from Trypanosoma brucei

Structural and Biochemical Analyses of the Eukaryotic Heat Shock Locus V (HslV) from Trypanosoma brucei

Unfolding the mechanism of the AAA+ unfoldase VAT by a combined cryo-EM, solution NMR study

The Final Moments of Misfolded Proteins en Route to the Proteasome

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