Abstract
Cullin E3 ligases are the largest family of ubiquitin ligases with diverse cellular functions. One of seven cullin proteins serves as a scaffold protein for the assembly of the multisubunit ubiquitin ligase complex. Cullin binds the RING domain protein Rbx1/Rbx2 via its C-terminus and a cullin-specific substrate adaptor protein via its N-terminus. In the Cul3 ubiquitin ligase complex, Cul3 substrate receptors contain a BTB/POZ domain. Several studies have established that Cul3-based E3 ubiquitin ligases exist in a dimeric state which is required for binding of a number of substrates and has been suggested to promote ubiquitin transfer. In two different models, Cul3 has been proposed to dimerize either via BTB/POZ domain dependent substrate receptor homodimerization or via direct interaction between two Cul3 proteins that is mediated by Nedd8 modification of one of the dimerization partners. In this study, we show that the majority of the Cul3 proteins in cells exist as dimers or multimers and that Cul3 self-association is mediated via the Cul3 N-terminus while the Cul3 C-terminus is not required. Furthermore, we show that Cul3 self-association is independent of its modification with Nedd8. Our results provide evidence for BTB substrate receptor dependent Cul3 dimerization which is likely to play an important role in promoting substrate ubiquitination.
Highlights
Cullin3 (Cul3) E3 ubiquitin ligases are involved in the recognition and recruitment of numerous important substrates for ubiquitination [1,2,3,4]
Dimerization is a key component of biological regulatory networks and is frequently employed in E3 ubiquitin ligases
RING finger protein 4 (RNF4), Anaphase Promoting Complex (APC) and C-terminal of Hsp70-interacting protein (CHIP) E3 ligases have been shown to exist in a dimeric state [32,33,34]
Summary
Cullin (Cul3) E3 ubiquitin ligases are involved in the recognition and recruitment of numerous important substrates for ubiquitination [1,2,3,4]. Cul dependent ubiquitination has emerged as a mechanism to control various critical cellular processes including the antioxidant response, cell migration, cell cycle progression and retrograde trafficking [3,5,6,7,8]. Absence of Cul has been reported to cause inhibition of cell migration in human and drosophila cells [3]. This is due to stabilization of the Cul substrate RhoA which controls actin cytoskeleton stress fiber development [3]. Cells with reduced Cul expression exhibit abnormal actin stress fibers and distorted cell morphology [3]
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