Molecular genetics of the ubiquitin-proteasome system: lessons from yeast.
Our studies with the yeast Saccharomyces cerevisiae have uncovered a number of general principles governing substrate selectivity and proteolysis by the ubiquitin-proteasome system. The initial work focused on the degradation of a transcription factor, the MATalpha2 repressor, but the pathways uncovered have a much broader range of targets. At least two distinct ubiquitination mechanisms contribute to alpha2 turnover. One of them depends on a large integral membrane ubiquitin ligase (E3) and a pair of ubiquitin-conjugating enzymes (E2s). The transmembrane E3 and E2 proteins must travel from their site of synthesis in the ER to the inner nuclear membrane in order to reach nuclear substrates such as alpha2. The 26S proteasome is responsible for alpha2 degradation, and several important features of proteasome assembly and active site formation were uncovered. Most recently, we have delineated major steps in 20S proteasome assembly and have also identified several novel 20S proteasome assembly factors. Surprisingly, alterations in 20S proteasome assembly lead to defects in the assembly of the proteasome regulatory particle (RP). The RP associates with the 20S proteasome to form the 26S proteasome. Our data suggest that the 20S proteasome can function as an assembly factor for the RP, which would make it the first such factor for RP assembly identified to date.
Hochstrasser
M
M
Department of Molecular Biophysics and Biochemistry, Yale University, 266 Whitney Avenue, P.O. Box 208114, New Haven, CT 06520-8114, USA. mark.hochstrasser@yale.edu
Deng
M
M
Kusmierczyk
A R
AR
Li
X
X
Kreft
S G
SG
Ravid
T
T
Funakoshi
M
M
Kunjappu
M
M
Xie
Y
Y
D000818:Animals; D006801:Humans; D008967:Molecular Biology; D046988:Proteasome Endopeptidase Complex / Q000235:genetics* / Q000378:metabolism*; D011485:Protein Binding; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism*; D013379:Substrate Specificity; D025801:Ubiquitin / Q000235:genetics* / Q000378:metabolism*
D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex