Head-to-tail interactions of the coiled-coil domains regulate ClpB activity and cooperation with Hsp70 in protein disaggregation

Carroni, Marta; Kummer, Eva; Oguchi, Yusuke; Wendler, Petra; Clare, Daniel K.; Sinning, Irmgard; Kopp, Jürgen; Mogk, Axel; Bukau, Bernd; Saibil, Helen R.

doi:10.7554/elife.02481

Cited by 121 publications

(223 citation statements)

References 60 publications

(145 reference statements)

Supporting

Mentioning

203

Contrasting

Order By: Relevance

“…8). Recently, Saibil and co-workers (45) showed that each AAAϩ ring of the EClpB hexamer simultaneously binds four ADP molecules. From this observation, the binding of four ATP molecules to one ring would be expected to activate the ATPase of another ring.…”

Section: Discussionmentioning

confidence: 99%

Analysis of the Cooperative ATPase Cycle of the AAA+ Chaperone ClpB from Thermus thermophilus by Using Ordered Heterohexamers with an Alternating Subunit Arrangement

Yamasaki

Oohata²,

Nakamura³

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: Ring-shaped ClpB hexamer hydrolyzes ATP and reactivates protein aggregates. Results: Intercalation of ATPase defective subunits into the hexamer every other subunit hampered its ATPase and disaggregation activities. Conclusion: ClpB cooperatively hydrolyzes ATP, and this cooperativity is crucial for protein disaggregation. Significance: This study presents a new method to study the cooperativity of homo-oligomeric proteins and provides insights into the common mechanism of AAAϩ ATPases.

show abstract

Section: Discussionmentioning

confidence: 99%

Analysis of the Cooperative ATPase Cycle of the AAA+ Chaperone ClpB from Thermus thermophilus by Using Ordered Heterohexamers with an Alternating Subunit Arrangement

Yamasaki

Oohata²,

Nakamura³

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Unfoldases bind to misfolded proteins and unfold them. [39] Disaggregases solubilize existing protein aggregates [370]. Some chaperones exhibit overlapping functions [371].…”

Section: Discussionmentioning

confidence: 99%

“…PDB IDs: Skp, 1SG2 [275]; trigger factor, 1W26 [19]; SecA, 2FSF [369]; Hsp90, 2CG9 [182]; GroEL/ES, 1AON [34]; ClpX, 3HWS [39]; ClpB, 4D2U [370]; DnaK, 4B9Q [371]; FhaC, 2QDZ [61]; BamA, 4K3B [64]; SecYEG, 3DIN [372]; TamA, 4C00 [67]; proteasome, 1YAR [75]; HslU/HslV, 1G3I [72]. See text and Table 1 for details.…”

Section: Figure Legendsmentioning

confidence: 99%

Chaperones and chaperone–substrate complexes: Dynamic playgrounds for NMR spectroscopists

Burmann¹,

Hiller²

2015

Progress in Nuclear Magnetic Resonance Spectroscopy

View full text Add to dashboard Cite

show abstract

“…2A) using a cross-linking approach. We used gentle glutaraldehyde cross-linking conditions that were previously used to establish the oligomeric state of the related AAA+ ATPase ClpB (22), which was independently confirmed by structural means (23). Following cross-linking for a duration that was just sufficient to deplete free cofactor and Torsin (t = 10 min), two major species were observed in a 6-9% gradient gel ( Fig.…”

Section: Significancementioning

confidence: 99%

The mechanism of Torsin ATPase activation

Brown

Zhao

Chase

et al. 2014

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

146

View full text Add to dashboard Cite

Torsins are membrane-associated ATPases whose activity is dependent on two activating cofactors, lamina-associated polypeptide 1 (LAP1) and luminal domain-like LAP1 (LULL1). The mechanism by which these cofactors regulate Torsin activity has so far remained elusive. In this study, we identify a conserved domain in these activators that is predicted to adopt a fold resembling an AAA+ (ATPase associated with a variety of cellular activities) domain. Within these domains, a strictly conserved Arg residue present in both activating cofactors, but notably missing in Torsins, aligns with a key catalytic Arg found in AAA+ proteins. We demonstrate that cofactors and Torsins associate to form heterooligomeric assemblies with a defined Torsin-activator interface. In this arrangement, the highly conserved Arg residue present in either cofactor comes into close proximity with the nucleotide bound in the neighboring Torsin subunit. Because this invariant Arg is strictly required to stimulate Torsin ATPase activity but is dispensable for Torsin binding, we propose that LAP1 and LULL1 regulate Torsin ATPase activity through an active site complementation mechanism.DYT1 dystonia | nuclear envelope | ATPase | Torsin T orsin ATPases belong to the AAA+ (ATPase associated with a variety of cellular activities) superfamily of ATPases (1) but are unusual in that they lack conserved catalytic residues that are typically found in related ATPases (2, 3). Accordingly, Torsins do not display ATPase activity unless they are engaged by their regulatory cofactors lamina-associated polypeptide 1 (LAP1) or luminal domain-like LAP1 (LULL1) (4), which are type II transmembrane proteins residing in the nuclear envelope and endoplasmic reticulum (ER) (5, 6). This property stands in sharp contrast to the behavior of closely related Clp/Hsp100 ATPases, which display considerable basal ATPase activities that are moderately stimulated by their substrates (7,8). Although a number of Clp/Hsp100 proteins use distinct cofactors that confer substrate specificity to the typically hexameric ATPase ring, they operate via similar principles (9). Substrates ultimately engage the pore at the center of the oligomeric assembly. This narrow annulus is defined by pore loops that emanate from each subunit and harbor a conserved aromatic residue that defines the center of the pore (10). The energy of ATP hydrolysis is invested in threading the substrate through this axial channel, and the substrate is unfolded in the process (11).Much less is known about the mode of action of Torsin ATPases, although it is clear that regulation of Torsin activity is of vital importance in an organismal context. A mutation in TorsinA (TorA) causing the movement disorder primary dystonia (12) renders TorA unresponsive to its binding partners LAP1 and LULL1 (4), and a homozygous "knock-in" of this disease allele in mice causes a lethal phenotype, as does a TorA KO (13). A conditional deletion of TorA from the CNS in mice accurately replicates the symptoms of primary dystonia (14). In add...

show abstract

Head-to-tail interactions of the coiled-coil domains regulate ClpB activity and cooperation with Hsp70 in protein disaggregation

Cited by 121 publications

References 60 publications

Analysis of the Cooperative ATPase Cycle of the AAA+ Chaperone ClpB from Thermus thermophilus by Using Ordered Heterohexamers with an Alternating Subunit Arrangement

Analysis of the Cooperative ATPase Cycle of the AAA+ Chaperone ClpB from Thermus thermophilus by Using Ordered Heterohexamers with an Alternating Subunit Arrangement

Chaperones and chaperone–substrate complexes: Dynamic playgrounds for NMR spectroscopists

The mechanism of Torsin ATPase activation

Contact Info

Product

Resources

About