Autoinhibition and relief mechanism for Polo-like kinase 4

Abstract

Polo-like kinase 4 (Plk4) is a master regulator of centriole duplication, and its hyperactivity induces centriole amplification. Homodimeric Plk4 has been shown to be ubiquitinated as a result of autophosphorylation, thus promoting its own degradation and preventing centriole amplification. Unlike other Plks, Plk4 contains three rather than two Polo box domains, and the function of its third Polo box (PB3) is unclear. Here, we performed a functional analysis of Plk4's structural domains. Like other Plks, Plk4 possesses a previously unidentified autoinhibitory mechanism mediated by a linker (L1) near the kinase domain. Thus, autoinhibition is a conserved feature of Plks. In the case of Plk4, autoinhibition is relieved after homodimerization and is accomplished by PB3 and by autophosphorylation of L1. In contrast, autophosphorylation of the second linker promotes separation of the Plk4 homodimer. Therefore, autoinhibition delays the multiple consequences of activation until Plk4 dimerizes. These findings reveal a complex mechanism of Plk4 regulation and activation which govern the process of centriole duplication.autoinhibition | centriole | centrosome | Polo box | Polo-like kinase 4

Cep78 is a new centriolar protein involved in Plk4-induced centriole overduplication

“…Our biochemical assays reveal that Cep78 interacts predominantly with the N-terminal domain of Plk4 and only weakly with the C-terminus. Given that the C-terminal Plk4 fragment heterodimerizes with full-length Plk4 (Klebba et al, 2015), it is conceivable that Cep78 was pulled out bound to the N-terminal part of full-length Plk4. We further established the interaction by immunoprecipitation of endogenous Cep78 and Plk4 (Fig.…”

KAT2A/KAT2B-targeted acetylome reveals a role for PLK4 acetylation in preventing centrosome amplification

“…Therefore, PLK4 protein levels and kinase activity must be tightly regulated. This is achieved in part by PLK4 protein stability being regulated by auto-phosphorylation, which triggers ubiquitin-mediated proteasomal degradation (reviewed in refs 28, 29, 30). Whereas the mechanisms regulating PLK4 activation, protein ubiquitination and degradation have been clarified, those modulating PLK4 kinase activity remain elusive.…”

Novel compound heterozygous variants in PLK4 identified in a patient with autosomal recessive microcephaly and chorioretinopathy

“…13 PLK4 has a kinase domain at its amino terminal and three PB domains mediating centriole localization and homodimerization at its carboxyl terminal. 14 PLK4 autophosphorylation regulates its activity, 15,16 which is strictly controlled in terms of timing and location during the cell cycle. 17 We have shown from our current analyses that the p.(C779Y) PLK4 variant lacks the normal function in centriole duplication.…”

“…It is thus probable that the p.(C779Y) variant in the PB2 domain impedes the homodimerization of PLK4 and consequently the loss of normal protein function due to the prevalence of the monomeric form. 16 On the other hand, the p.(M148V) variant in the kinase domain of PLK4 could amplify the number of centrioles at WT levels when overexpressed in HeLa cells. It is therefore possible that the overexpressed p.(M148V) variant does not reduce the overall kinase activity levels of PLK4 in the presence of the WT protein even if it lacks kinase activity itself.…”