A Role for the Fizzy/Cdc20 Family of Proteins in Activation of the APC/C Distinct from Substrate Recruitment

Cell Cycle Control Laboratory, Marie Curie Research Institute, The Chart, Oxted, RH8 0TL Surrey, UK.
Molecular cell (Impact Factor: 14.46). 12/2008; 32(4):576-83. DOI: 10.1016/j.molcel.2008.09.023
Source: PubMed

ABSTRACT The Fizzy/Cdc20 family of proteins are essential activators of the anaphase-promoting complex/cyclosome (APC/C), a multisubunit E3 ubiquitin ligase. However, apart from the well-established role of the C-terminal WD40 domain in substrate recognition, the precise roles of the activators remain elusive. Here we show that Nek2A, which directly binds the APC/C, can be ubiquitylated and destroyed in Fizzy/Cdc20-depleted Xenopus egg extracts when only the N-terminal domain of Fizzy/Cdc20 (N-Cdc20) is added. This activity is dependent upon the C box and is conserved in the alternative activator, Fizzy-related/Cdh1. In contrast, canonical substrates such as cyclin B and securin require both the N-terminal and WD40 domains, unless N-Cdc20 is fused to substrates when the WD40 domain becomes dispensable. Furthermore, in Cdc20-depleted cells, N-Cdc20 can facilitate Nek2A destruction in a C box-dependent manner. Our results reveal a role for the N-terminal domain of the Fizzy/Cdc20 family of activators in triggering substrate ubiquitylation by the APC/C.

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Available from: Hiro Yamano, Jun 29, 2015