An unstructured initiation site is required for efficient proteasome-mediated degradation

被引:354
作者
Prakash, S
Tian, L
Ratliff, KS
Lehotzky, RE
Matouschek, A
机构
[1] Northwestern Univ, Dept Biochem Mol Biol & Cell Biol, Evanston, IL 60208 USA
[2] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA
关键词
D O I
10.1038/nsmb814
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The proteasome is the main ATP-dependent protease in eukaryotic cells and controls the concentration of many regulatory proteins in the cytosol and nucleus. Proteins are targeted to the proteasome by the covalent attachment of polyubiquitin chains. The ubiquitin modification serves as the proteasome recognition element but by itself is not sufficient for efficient degradation of folded proteins. We report that proteolysis of tightly folded proteins is accelerated greatly when an unstructured region is attached to the substrate. The unstructured region serves as the initiation site for degradation and is hydrolyzed first, after which the rest of the protein is digested sequentially. These results identify the initiation site as a novel component of the targeting signal, which is required to engage the proteasome unfolding machinery efficiently. The proteasome degrades a substrate by first binding to its ubiquitin modification and then initiating unfolding at an unstructured region.
引用
收藏
页码:830 / 837
页数:8
相关论文
共 53 条
[1]   Ubiquitylation of BAG-1 suggests a novel regulatory mechanism during the sorting of chaperone substrates to the proteasome [J].
Alberti, S ;
Demand, J ;
Esser, C ;
Emmerich, N ;
Schild, H ;
Höhfeld, J .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (48) :45920-45927
[2]   THE DEGRADATION SIGNAL IN A SHORT-LIVED PROTEIN [J].
BACHMAIR, A ;
VARSHAVSKY, A .
CELL, 1989, 56 (06) :1019-1032
[3]   INVIVO HALF-LIFE OF A PROTEIN IS A FUNCTION OF ITS AMINO-TERMINAL RESIDUE [J].
BACHMAIR, A ;
FINLEY, D ;
VARSHAVSKY, A .
SCIENCE, 1986, 234 (4773) :179-186
[4]   The proteasome:: Paradigm of a self-compartmentalizing protease [J].
Baumeister, W ;
Walz, J ;
Zühl, F ;
Seemuller, E .
CELL, 1998, 92 (03) :367-380
[5]   The base of the proteasome regulatory particle exhibits chaperone-like activity [J].
Braun, BC ;
Glickman, M ;
Kraft, R ;
Dahlmann, B ;
Kloetzel, PM ;
Finley, D ;
Schmidt, M .
NATURE CELL BIOLOGY, 1999, 1 (04) :221-226
[6]   A novel site for ubiquitination: the N-terminal residue, and not internal lysines of MyoD, is essential for conjugation and degradation of the protein [J].
Breitschopf, K ;
Bengal, E ;
Ziv, T ;
Admon, A ;
Ciechanover, A .
EMBO JOURNAL, 1998, 17 (20) :5964-5973
[7]   Involvement of valosin-containing protein, an ATPase co-purified with IκBα and 26 S proteasome, in ubiquitin-proteasome-mediated degradation of IκBα [J].
Dai, RM ;
Chen, EY ;
Longo, DL ;
Gorbea, CM ;
Li, CCH .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (06) :3562-3573
[8]   Helicase mechanisms and the coupling of helicases within macromolecular machines Part 1: Structures and properties of isolated helicases [J].
Delagoutte, E ;
von Hippel, PH .
QUARTERLY REVIEWS OF BIOPHYSICS, 2002, 35 (04) :431-478
[9]  
DEVERAUX Q, 1994, J BIOL CHEM, V269, P7059
[10]   Proteasome subunit Rpn1 binds ubiquitin-like protein domains [J].
Elsasser, S ;
Gali, RR ;
Schwickart, M ;
Larsen, CN ;
Leggett, DS ;
Müller, B ;
Feng, MT ;
Tübing, F ;
Dittmar, GAG ;
Finley, D .
NATURE CELL BIOLOGY, 2002, 4 (09) :725-730