title: Ubiquitinated proteins activate the proteasomal ATPases by binding to Usp14 or Uch37 homologs.
abstract: Degradation of ubiquitinated proteins by 26 S proteasomes requires ATP hydrolysis, but it is unclear how the proteasomal ATPases are regulated and how proteolysis, substrate deubiquitination, degradation, and ATP hydrolysis are coordinated. Polyubiquitinated proteins were shown to stimulate ATP hydrolysis by purified proteasomes, but only if the proteins contain a loosely folded domain. If they were not ubiquitinated, such proteins did not increase ATPase activity. However, they did so upon addition of ubiquitin aldehyde, which mimics the ubiquitin chain and binds to 26 S-associated deubiquitinating enzymes (DUBs): in yeast to Ubp6, which is essential for the ATPase activation, and in mammalian 26 S to the Ubp6 homolog, Usp14, and Uch37. Occupancy of either DUB by a ubiquitin conjugate leads to ATPase stimulation, thereby coupling deubiquitination and ATP hydrolysis. Thus, ubiquitinated loosely folded proteins, after becoming bound to the 26 S, interact with Ubp6/Usp14 or Uch37 to activate ATP hydrolysis and enhance their own destruction.
authors: Harvard Medical School, Boston, Massachusetts 02115.
authors: Andreas
authors: A
authors: Peth
authors: Harvard Medical School, Boston, Massachusetts 02115.
authors: Nikolay
authors: N
authors: Kukushkin
authors: Inbiomed, Paeso Mikeltegi, 81 San Sebastián, Gipuzkoa 20009, Spain.
authors: Marc
authors: M
authors: Bossé
authors: Harvard Medical School, Boston, Massachusetts 02115. Electronic address: Alfred_goldberg@hms.harvard.edu.
authors: Alfred L
authors: AL
authors: Goldberg
mesh_terms: D000251:Adenosine Triphosphatases / Q000737:chemistry*; D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D002268:Carboxypeptidases / Q000737:chemistry*; D005347:Fibroblasts / Q000378:metabolism; D005656:Fungal Proteins; D015971:Gene Expression Regulation, Enzymologic; D006868:Hydrolysis; D051379:Mice; D008954:Models, Biological; D008968:Molecular Conformation; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D011817:Rabbits; D025801:Ubiquitin / Q000737:chemistry*; D043222:Ubiquitin Thiolesterase / Q000737:chemistry*
chemical_list: D005656:Fungal Proteins; D025801:Ubiquitin; C469268:Usp14 protein, mouse; D000255:Adenosine Triphosphate; D002268:Carboxypeptidases; D043222:Ubiquitin Thiolesterase; C581032:Uchl5 protein, mouse; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D000251:Adenosine Triphosphatases