National Institutes of Health/National Human Genome Research Institute
R01GM074074
米国
National Institutes of Health/National Human Genome Research Institute
P41GM103832
米国
National Institutes of Health/National Human Genome Research Institute
F32GM103124
米国
National Institutes of Health/National Human Genome Research Institute
P01NS092525
米国
National Institutes of Health/National Human Genome Research Institute
R01GM079429
米国
European Research Council
AdvG #670821
ドイツ
European Research Council
AdvG #233226
ドイツ
引用
ジャーナル: Cell / 年: 2019 タイトル: The Chaperonin TRiC/CCT Associates with Prefoldin through a Conserved Electrostatic Interface Essential for Cellular Proteostasis. 著者: Daniel Gestaut / Soung Hun Roh / Boxue Ma / Grigore Pintilie / Lukasz A Joachimiak / Alexander Leitner / Thomas Walzthoeni / Ruedi Aebersold / Wah Chiu / Judith Frydman / 要旨: Maintaining proteostasis in eukaryotic protein folding involves cooperation of distinct chaperone systems. To understand how the essential ring-shaped chaperonin TRiC/CCT cooperates with the ...Maintaining proteostasis in eukaryotic protein folding involves cooperation of distinct chaperone systems. To understand how the essential ring-shaped chaperonin TRiC/CCT cooperates with the chaperone prefoldin/GIMc (PFD), we integrate cryoelectron microscopy (cryo-EM), crosslinking-mass-spectrometry and biochemical and cellular approaches to elucidate the structural and functional interplay between TRiC/CCT and PFD. We find these hetero-oligomeric chaperones associate in a defined architecture, through a conserved interface of electrostatic contacts that serves as a pivot point for a TRiC-PFD conformational cycle. PFD alternates between an open "latched" conformation and a closed "engaged" conformation that aligns the PFD-TRiC substrate binding chambers. PFD can act after TRiC bound its substrates to enhance the rate and yield of the folding reaction, suppressing non-productive reaction cycles. Disrupting the TRiC-PFD interaction in vivo is strongly deleterious, leading to accumulation of amyloid aggregates. The supra-chaperone assembly formed by PFD and TRiC is essential to prevent toxic conformations and ensure effective cellular proteostasis.