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STIL binding to Polo-box 3 of PLK4 regulates centriole duplication.

Arquint C, Gabryjonczyk AM, Imseng S, Böhm R, Sauer E, Hiller S, Nigg EA, Maier T - Elife (2015)

Bottom Line: STIL-CC is the first identified interaction partner of Polo-box 3 (PB3) of PLK4 and also uses a secondary interaction site in the PLK4 L1 region.In vivo analysis of structure-guided STIL mutants reveals distinct binding modes to PLK4-PB3 and L1, as well as interplay of STIL oligomerization with PLK4 binding.We suggest that the STIL-CC/PLK4 interaction mediates PLK4 activation as well as stabilization of centriolar PLK4 and plays a key role in centriole duplication.

View Article: PubMed Central - PubMed

Affiliation: Biozentrum, University of Basel, Basel, Switzerland.

ABSTRACT
Polo-like kinases (PLK) are eukaryotic regulators of cell cycle progression, mitosis and cytokinesis; PLK4 is a master regulator of centriole duplication. Here, we demonstrate that the SCL/TAL1 interrupting locus (STIL) protein interacts via its coiled-coil region (STIL-CC) with PLK4 in vivo. STIL-CC is the first identified interaction partner of Polo-box 3 (PB3) of PLK4 and also uses a secondary interaction site in the PLK4 L1 region. Structure determination of free PLK4-PB3 and its STIL-CC complex via NMR and crystallography reveals a novel mode of Polo-box-peptide interaction mimicking coiled-coil formation. In vivo analysis of structure-guided STIL mutants reveals distinct binding modes to PLK4-PB3 and L1, as well as interplay of STIL oligomerization with PLK4 binding. We suggest that the STIL-CC/PLK4 interaction mediates PLK4 activation as well as stabilization of centriolar PLK4 and plays a key role in centriole duplication.

No MeSH data available.


Related in: MedlinePlus

STIL binding to PLK4 regulates centriole duplication.Hypothetical mechanism for STIL-mediated PLK4 activation: (1) PLK4 is bound to the mother centriole. It is intrinsically inactive, likely due to an autoinhibition by linker L1. (2a) STIL binds to PLK4 that has been recruited to centrioles through interactions with CEP192 and/or Cep152. (2b) STIL binding relieves the autoinhibition of PLK4, thus activating PLK4. (3) Activated PLK4 phosphorylates STIL in the STAN motif, which induces SAS-6 recruitment and daughter centriole biogenesis (4). Activated PLK4 also phosphorylates neighboring PLK4s in the degradation motif, triggering their degradation. At the site of cartwheel formation, the STIL-bound PLK4 is protected against degradation.DOI:http://dx.doi.org/10.7554/eLife.07888.019
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fig7: STIL binding to PLK4 regulates centriole duplication.Hypothetical mechanism for STIL-mediated PLK4 activation: (1) PLK4 is bound to the mother centriole. It is intrinsically inactive, likely due to an autoinhibition by linker L1. (2a) STIL binds to PLK4 that has been recruited to centrioles through interactions with CEP192 and/or Cep152. (2b) STIL binding relieves the autoinhibition of PLK4, thus activating PLK4. (3) Activated PLK4 phosphorylates STIL in the STAN motif, which induces SAS-6 recruitment and daughter centriole biogenesis (4). Activated PLK4 also phosphorylates neighboring PLK4s in the degradation motif, triggering their degradation. At the site of cartwheel formation, the STIL-bound PLK4 is protected against degradation.DOI:http://dx.doi.org/10.7554/eLife.07888.019

Mentions: Recent studies have revealed a regulatory role for PB3 in the activation of SAK/PLK4 in Drosophila (Klebba et al., 2015). Specifically, it was suggested that PB3, autophosphorylation of L1, and potentially further yet unidentified protein partners are important for relief of kinase auto-inhibition after SAK/PLK4 homodimerization. Our data on human PLK4 suggest to attribute a key role in such regulatory mechanism to STIL: first, STIL is the only identified interaction partner of PB3 with a direct influence on PB3 structure and dynamics; second, through its CC domain STIL is also able to interact with purported regulatory regions within L1 of human PLK4. These features make STIL a prime candidate for the role of an external factor regulating relief of PLK4 auto-inhibition in time and space (Figure 7, upper panel).10.7554/eLife.07888.019Figure 7.STIL binding to PLK4 regulates centriole duplication.


STIL binding to Polo-box 3 of PLK4 regulates centriole duplication.

Arquint C, Gabryjonczyk AM, Imseng S, Böhm R, Sauer E, Hiller S, Nigg EA, Maier T - Elife (2015)

STIL binding to PLK4 regulates centriole duplication.Hypothetical mechanism for STIL-mediated PLK4 activation: (1) PLK4 is bound to the mother centriole. It is intrinsically inactive, likely due to an autoinhibition by linker L1. (2a) STIL binds to PLK4 that has been recruited to centrioles through interactions with CEP192 and/or Cep152. (2b) STIL binding relieves the autoinhibition of PLK4, thus activating PLK4. (3) Activated PLK4 phosphorylates STIL in the STAN motif, which induces SAS-6 recruitment and daughter centriole biogenesis (4). Activated PLK4 also phosphorylates neighboring PLK4s in the degradation motif, triggering their degradation. At the site of cartwheel formation, the STIL-bound PLK4 is protected against degradation.DOI:http://dx.doi.org/10.7554/eLife.07888.019
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4530586&req=5

fig7: STIL binding to PLK4 regulates centriole duplication.Hypothetical mechanism for STIL-mediated PLK4 activation: (1) PLK4 is bound to the mother centriole. It is intrinsically inactive, likely due to an autoinhibition by linker L1. (2a) STIL binds to PLK4 that has been recruited to centrioles through interactions with CEP192 and/or Cep152. (2b) STIL binding relieves the autoinhibition of PLK4, thus activating PLK4. (3) Activated PLK4 phosphorylates STIL in the STAN motif, which induces SAS-6 recruitment and daughter centriole biogenesis (4). Activated PLK4 also phosphorylates neighboring PLK4s in the degradation motif, triggering their degradation. At the site of cartwheel formation, the STIL-bound PLK4 is protected against degradation.DOI:http://dx.doi.org/10.7554/eLife.07888.019
Mentions: Recent studies have revealed a regulatory role for PB3 in the activation of SAK/PLK4 in Drosophila (Klebba et al., 2015). Specifically, it was suggested that PB3, autophosphorylation of L1, and potentially further yet unidentified protein partners are important for relief of kinase auto-inhibition after SAK/PLK4 homodimerization. Our data on human PLK4 suggest to attribute a key role in such regulatory mechanism to STIL: first, STIL is the only identified interaction partner of PB3 with a direct influence on PB3 structure and dynamics; second, through its CC domain STIL is also able to interact with purported regulatory regions within L1 of human PLK4. These features make STIL a prime candidate for the role of an external factor regulating relief of PLK4 auto-inhibition in time and space (Figure 7, upper panel).10.7554/eLife.07888.019Figure 7.STIL binding to PLK4 regulates centriole duplication.

Bottom Line: STIL-CC is the first identified interaction partner of Polo-box 3 (PB3) of PLK4 and also uses a secondary interaction site in the PLK4 L1 region.In vivo analysis of structure-guided STIL mutants reveals distinct binding modes to PLK4-PB3 and L1, as well as interplay of STIL oligomerization with PLK4 binding.We suggest that the STIL-CC/PLK4 interaction mediates PLK4 activation as well as stabilization of centriolar PLK4 and plays a key role in centriole duplication.

View Article: PubMed Central - PubMed

Affiliation: Biozentrum, University of Basel, Basel, Switzerland.

ABSTRACT
Polo-like kinases (PLK) are eukaryotic regulators of cell cycle progression, mitosis and cytokinesis; PLK4 is a master regulator of centriole duplication. Here, we demonstrate that the SCL/TAL1 interrupting locus (STIL) protein interacts via its coiled-coil region (STIL-CC) with PLK4 in vivo. STIL-CC is the first identified interaction partner of Polo-box 3 (PB3) of PLK4 and also uses a secondary interaction site in the PLK4 L1 region. Structure determination of free PLK4-PB3 and its STIL-CC complex via NMR and crystallography reveals a novel mode of Polo-box-peptide interaction mimicking coiled-coil formation. In vivo analysis of structure-guided STIL mutants reveals distinct binding modes to PLK4-PB3 and L1, as well as interplay of STIL oligomerization with PLK4 binding. We suggest that the STIL-CC/PLK4 interaction mediates PLK4 activation as well as stabilization of centriolar PLK4 and plays a key role in centriole duplication.

No MeSH data available.


Related in: MedlinePlus