TY - JOUR
T1 - Operational plasticity enables Hsp104 to disaggregate diverse amyloid and nonamyloid clients
AU - Desantis, Morgan E.
AU - Leung, Eunice H.
AU - Sweeny, Elizabeth A.
AU - Jackrel, Meredith E.
AU - Cushman-Nick, Mimi
AU - Neuhaus-Follini, Alexandra
AU - Vashist, Shilpa
AU - Sochor, Matthew A.
AU - Knight, M. Noelle
AU - Shorter, James
N1 - Funding Information:
We thank Sue Lindquist, Sabine Kedzierska-Mieszkowska, and Virginia Lee for reagents. We thank Sandra Maday, Mark Lemmon, Aaron Gitler, Walter Englander, and Nancy Bonini for critiques and Lili Guo for artwork. Our work was funded by NIH training grant T32GM071339 and NRSA predoctoral fellowship F31NS079009 (M.E.D.); NIH training grant T32GM008275 (E.A.S. and M.A.S.); AHA predoctoral (E.A.S.) and postdoctoral fellowships (M.E.J.); NIH training grant T32AG000255 and NRSA predoctoral fellowship F31NS067890 (M.C.-N.); NIH Director’s New Innovator Award (DP2OD002177), Ellison Medical Foundation New Scholar in Aging Award, Penn Institute of Aging, Alzheimer Disease Core Center, and Diabetes Research Center Awards (J.S.).
PY - 2012/11/9
Y1 - 2012/11/9
N2 - It is not understood how Hsp104, a hexameric AAA+ ATPase from yeast, disaggregates diverse structures, including stress-induced aggregates, prions, and α-synuclein conformers connected to Parkinson disease. Here, we establish that Hsp104 hexamers adapt different mechanisms of intersubunit collaboration to disaggregate stress-induced aggregates versus amyloid. To resolve disordered aggregates, Hsp104 subunits collaborate noncooperatively via probabilistic substrate binding and ATP hydrolysis. To disaggregate amyloid, several subunits cooperatively engage substrate and hydrolyze ATP. Importantly, Hsp104 variants with impaired intersubunit communication dissolve disordered aggregates, but not amyloid. Unexpectedly, prokaryotic ClpB subunits collaborate differently than Hsp104 and couple probabilistic substrate binding to cooperative ATP hydrolysis, which enhances disordered aggregate dissolution but sensitizes ClpB to inhibition and diminishes amyloid disaggregation. Finally, we establish that Hsp104 hexamers deploy more subunits to disaggregate Sup35 prion strains with more stable "cross-β" cores. Thus, operational plasticity enables Hsp104 to robustly dissolve amyloid and nonamyloid clients, which impose distinct mechanical demands.
AB - It is not understood how Hsp104, a hexameric AAA+ ATPase from yeast, disaggregates diverse structures, including stress-induced aggregates, prions, and α-synuclein conformers connected to Parkinson disease. Here, we establish that Hsp104 hexamers adapt different mechanisms of intersubunit collaboration to disaggregate stress-induced aggregates versus amyloid. To resolve disordered aggregates, Hsp104 subunits collaborate noncooperatively via probabilistic substrate binding and ATP hydrolysis. To disaggregate amyloid, several subunits cooperatively engage substrate and hydrolyze ATP. Importantly, Hsp104 variants with impaired intersubunit communication dissolve disordered aggregates, but not amyloid. Unexpectedly, prokaryotic ClpB subunits collaborate differently than Hsp104 and couple probabilistic substrate binding to cooperative ATP hydrolysis, which enhances disordered aggregate dissolution but sensitizes ClpB to inhibition and diminishes amyloid disaggregation. Finally, we establish that Hsp104 hexamers deploy more subunits to disaggregate Sup35 prion strains with more stable "cross-β" cores. Thus, operational plasticity enables Hsp104 to robustly dissolve amyloid and nonamyloid clients, which impose distinct mechanical demands.
UR - http://www.scopus.com/inward/record.url?scp=84869017593&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2012.09.038
DO - 10.1016/j.cell.2012.09.038
M3 - Article
C2 - 23141537
AN - SCOPUS:84869017593
SN - 0092-8674
VL - 151
SP - 778
EP - 793
JO - Cell
JF - Cell
IS - 4
ER -