ATP-dependent proteases degrade their substrates by processively unraveling them from the degradation signal.
Protein unfolding is a key step in several cellular processes, including protein translocation across some membranes and protein degradation by ATP-dependent proteases. ClpAP protease and the proteasome can actively unfold proteins in a process that hydrolyzes ATP. Here we show that these proteases seem to catalyze unfolding by processively unraveling their substrates from the attachment point of the degradation signal. As a consequence, the ability of a protein to be degraded depends on its structure as well as its stability. In multidomain proteins, independently stable domains are unfolded sequentially. We show that these results can explain the limited degradation by the proteasome that occurs in the processing of the precursor of the transcription factor NF-kappaB.
Lee
C
C
Department of Biochemistry, Molecular Biology, and Cell Biology, Northwestern University, Evanston, Illinois 60208, USA.
Schwartz
M P
MP
Prakash
S
S
Iwakura
M
M
Matouschek
A
A
D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001426:Bacterial Proteins; D003546:Cysteine Endopeptidases / Q000378:metabolism; D049071:Endopeptidase Clp; D019286:Endopeptidase K / Q000378:metabolism; D004795:Enzyme Stability; D007700:Kinetics; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D009097:Multienzyme Complexes / Q000378:metabolism; D016328:NF-kappa B / Q000737:chemistry / Q000378:metabolism; D052002:NF-kappa B p50 Subunit; D046988:Proteasome Endopeptidase Complex; D011489:Protein Denaturation; D017510:Protein Folding; D011498:Protein Precursors / Q000737:chemistry / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D012260:Ribonucleases / Q000737:chemistry / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D012697:Serine Endopeptidases / Q000378:metabolism*; D013379:Substrate Specificity; D013696:Temperature; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000378:metabolism; D013816:Thermodynamics; D014452:Ubiquitins / Q000378:metabolism
D001426:Bacterial Proteins; D008024:Ligands; D009097:Multienzyme Complexes; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D011498:Protein Precursors; D014452:Ubiquitins; D000255:Adenosine Triphosphate; D013762:Tetrahydrofolate Dehydrogenase; D012260:Ribonucleases; C019760:Bacillus amyloliquefaciens ribonuclease; D012697:Serine Endopeptidases; D019286:Endopeptidase K; D049071:Endopeptidase Clp; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D000251:Adenosine Triphosphatases