International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)


B24. Regulation of SCF Ubiquitin-Ligase Complex by NEDD8/Rub1-Ligating System

Tomoki Chiba and Keiji Tanaka
The Tokyo Metropolitan Institute of Medical Science, and CREST, Japan Science and Technology Corporation (JST)

The SCF (Skp1, Cullin-1 or Cdc53, F-box protein) complex, consisting of common subunits (Skp1, Cullin-1, Roc1/Rbx1/Hrt1) and a variable subunit (substrate-recognition adaptor called F-box protein), functions as a E3 ubiquitin (Ub)-protein ligase that ubiquitylates a number of cellular proteins for degradation, and regulates multiple biologically important processes, such as the cell cycle and signal transduction. Cullin-1 is known to be covalently ligated by NEDD8/Rub1, a ubiquitin-like protein, by a multi-enzymatic system consisting of heterodimeric NEDD8-activating enzyme composed of APP-BP1 and Uba3, and NEDD8-conjugating enzyme Ubc12, in a manner analogous to the ubiquitylation reaction. Further biochemical and genetic analyses of the NEDD8 system revealed that NEDD8 modifies all member of Cullin family proteins in eukaryotes, and it cooperates with the SCF complex in yeast and plant, although the mechanistic role of NEDD8 modification or its essentiality was unclear. To investigate the role of the NEDD8 system toward SCF function at molecular level, we developed a complete in vitro reconstitution system of SCF complex that ubiquitylates I-kBa in a phosphorylation dependent manner. From these results in vitro and in vivo, we propose that NEDD8 system enhances the ubiquitylation activity of the SCF complex without affecting its complex assembly or substrate-binding. Furthermore, whereas NEDD8 system is not essential in budding yeast, we show that it is essential for the viability and the functions of Cullin family protein in mice. This is the first report of the important role of Ub-like protein that is involved in protein ubiquitylation through activation of the target proteins.


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