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Molecular basis for unidirectional scaffold switching of human Plk4 in centriole biogenesis.

Park SY, Park JE, Kim TS, Kim JH, Kwak MJ, Ku B, Tian L, Murugan RN, Ahn M, Komiya S, Hojo H, Kim NH, Kim BY, Bang JK, Erikson RL, Lee KW, Kim SJ, Oh BH, Yang W, Lee KS - Nat. Struct. Mol. Biol. (2014)

Bottom Line: Crystal-structure analyses revealed that Cep192- and Cep152-derived peptides bind the cryptic polo box (CPB) of Plk4 in opposite orientations and in a mutually exclusive manner.The Cep152 peptide bound to the CPB markedly better than did the Cep192 peptide and effectively 'snatched' the CPB away from a preformed CPB-Cep192 peptide complex.A cancer-associated Cep152 mutation impairing the Plk4 interaction induced defects in procentriole assembly and chromosome segregation.

View Article: PubMed Central - PubMed

Affiliation: 1] Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. [2] Advanced Institutes of Convergence Technology, Seoul National University, Suwon, Republic of Korea. [3].

ABSTRACT
Polo-like kinase 4 (Plk4) is a key regulator of centriole duplication, an event critical for the maintenance of genomic integrity. We show that Plk4 relocalizes from the inner Cep192 ring to the outer Cep152 ring as newly recruited Cep152 assembles around the Cep192-encircled daughter centriole. Crystal-structure analyses revealed that Cep192- and Cep152-derived peptides bind the cryptic polo box (CPB) of Plk4 in opposite orientations and in a mutually exclusive manner. The Cep152 peptide bound to the CPB markedly better than did the Cep192 peptide and effectively 'snatched' the CPB away from a preformed CPB-Cep192 peptide complex. A cancer-associated Cep152 mutation impairing the Plk4 interaction induced defects in procentriole assembly and chromosome segregation. Thus, Plk4 is intricately regulated in time and space through ordered interactions with two distinct scaffolds, Cep192 and Cep152, and a failure in this process may lead to human cancer.

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A schematic diagram illustrating the mechanism of how Cep152 snatches Plk4 away from the Cep192–Plk4 complex and repositions Plk4 at the outer boundary of a newly formed Cep152 ring structure. Early G1 daughter centrioles are decorated with a cylindrical Cep192 structure, in which the N-terminus of Cep192 points outward (Supplementary Figure 1a). At this stage, Plk4 forms a smaller (~440 nm outer diameter) ring through the interaction with the N-terminal region of Cep192 (see Supplementary Figure 1). As Cep152 is being recruited to this location in late G1, Cep152 stochastically interacts with the Cep192-bound Plk4 and snatches the Plk4 away from the Cep192 scaffold (scaffold switching). Subsequent assembly of a Cep152 ring around the Cep192 toroid in an N-terminus outward fashion prompts the repositioning of Plk4 to the outer edge of the Cep152 ring, thus resulting in a much larger Plk4 ring structure in diameter (~600 nm). Around the time of procentriole formation, Plk4 assumes a dot-like signal at the future procentriole assembly site and recruits Sas6 to this site to induce centriole biogenesis.
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Figure 5: A schematic diagram illustrating the mechanism of how Cep152 snatches Plk4 away from the Cep192–Plk4 complex and repositions Plk4 at the outer boundary of a newly formed Cep152 ring structure. Early G1 daughter centrioles are decorated with a cylindrical Cep192 structure, in which the N-terminus of Cep192 points outward (Supplementary Figure 1a). At this stage, Plk4 forms a smaller (~440 nm outer diameter) ring through the interaction with the N-terminal region of Cep192 (see Supplementary Figure 1). As Cep152 is being recruited to this location in late G1, Cep152 stochastically interacts with the Cep192-bound Plk4 and snatches the Plk4 away from the Cep192 scaffold (scaffold switching). Subsequent assembly of a Cep152 ring around the Cep192 toroid in an N-terminus outward fashion prompts the repositioning of Plk4 to the outer edge of the Cep152 ring, thus resulting in a much larger Plk4 ring structure in diameter (~600 nm). Around the time of procentriole formation, Plk4 assumes a dot-like signal at the future procentriole assembly site and recruits Sas6 to this site to induce centriole biogenesis.

Mentions: We showed that Cep152 recruitment induces Plk4 relocation from the outer edge of the Cep192 ring to that of the Cep152 ring (Fig. 1), suggesting that Plk4 translocates unidirectionally from the Cep192 scaffold to the Cep152 scaffold. In support of this interpretation, Cep152-60mer was able to efficiently snatch the CPB from the Cep192-58mer–CPB complex (Figs. 4d and 5).


Molecular basis for unidirectional scaffold switching of human Plk4 in centriole biogenesis.

Park SY, Park JE, Kim TS, Kim JH, Kwak MJ, Ku B, Tian L, Murugan RN, Ahn M, Komiya S, Hojo H, Kim NH, Kim BY, Bang JK, Erikson RL, Lee KW, Kim SJ, Oh BH, Yang W, Lee KS - Nat. Struct. Mol. Biol. (2014)

A schematic diagram illustrating the mechanism of how Cep152 snatches Plk4 away from the Cep192–Plk4 complex and repositions Plk4 at the outer boundary of a newly formed Cep152 ring structure. Early G1 daughter centrioles are decorated with a cylindrical Cep192 structure, in which the N-terminus of Cep192 points outward (Supplementary Figure 1a). At this stage, Plk4 forms a smaller (~440 nm outer diameter) ring through the interaction with the N-terminal region of Cep192 (see Supplementary Figure 1). As Cep152 is being recruited to this location in late G1, Cep152 stochastically interacts with the Cep192-bound Plk4 and snatches the Plk4 away from the Cep192 scaffold (scaffold switching). Subsequent assembly of a Cep152 ring around the Cep192 toroid in an N-terminus outward fashion prompts the repositioning of Plk4 to the outer edge of the Cep152 ring, thus resulting in a much larger Plk4 ring structure in diameter (~600 nm). Around the time of procentriole formation, Plk4 assumes a dot-like signal at the future procentriole assembly site and recruits Sas6 to this site to induce centriole biogenesis.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4125498&req=5

Figure 5: A schematic diagram illustrating the mechanism of how Cep152 snatches Plk4 away from the Cep192–Plk4 complex and repositions Plk4 at the outer boundary of a newly formed Cep152 ring structure. Early G1 daughter centrioles are decorated with a cylindrical Cep192 structure, in which the N-terminus of Cep192 points outward (Supplementary Figure 1a). At this stage, Plk4 forms a smaller (~440 nm outer diameter) ring through the interaction with the N-terminal region of Cep192 (see Supplementary Figure 1). As Cep152 is being recruited to this location in late G1, Cep152 stochastically interacts with the Cep192-bound Plk4 and snatches the Plk4 away from the Cep192 scaffold (scaffold switching). Subsequent assembly of a Cep152 ring around the Cep192 toroid in an N-terminus outward fashion prompts the repositioning of Plk4 to the outer edge of the Cep152 ring, thus resulting in a much larger Plk4 ring structure in diameter (~600 nm). Around the time of procentriole formation, Plk4 assumes a dot-like signal at the future procentriole assembly site and recruits Sas6 to this site to induce centriole biogenesis.
Mentions: We showed that Cep152 recruitment induces Plk4 relocation from the outer edge of the Cep192 ring to that of the Cep152 ring (Fig. 1), suggesting that Plk4 translocates unidirectionally from the Cep192 scaffold to the Cep152 scaffold. In support of this interpretation, Cep152-60mer was able to efficiently snatch the CPB from the Cep192-58mer–CPB complex (Figs. 4d and 5).

Bottom Line: Crystal-structure analyses revealed that Cep192- and Cep152-derived peptides bind the cryptic polo box (CPB) of Plk4 in opposite orientations and in a mutually exclusive manner.The Cep152 peptide bound to the CPB markedly better than did the Cep192 peptide and effectively 'snatched' the CPB away from a preformed CPB-Cep192 peptide complex.A cancer-associated Cep152 mutation impairing the Plk4 interaction induced defects in procentriole assembly and chromosome segregation.

View Article: PubMed Central - PubMed

Affiliation: 1] Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. [2] Advanced Institutes of Convergence Technology, Seoul National University, Suwon, Republic of Korea. [3].

ABSTRACT
Polo-like kinase 4 (Plk4) is a key regulator of centriole duplication, an event critical for the maintenance of genomic integrity. We show that Plk4 relocalizes from the inner Cep192 ring to the outer Cep152 ring as newly recruited Cep152 assembles around the Cep192-encircled daughter centriole. Crystal-structure analyses revealed that Cep192- and Cep152-derived peptides bind the cryptic polo box (CPB) of Plk4 in opposite orientations and in a mutually exclusive manner. The Cep152 peptide bound to the CPB markedly better than did the Cep192 peptide and effectively 'snatched' the CPB away from a preformed CPB-Cep192 peptide complex. A cancer-associated Cep152 mutation impairing the Plk4 interaction induced defects in procentriole assembly and chromosome segregation. Thus, Plk4 is intricately regulated in time and space through ordered interactions with two distinct scaffolds, Cep192 and Cep152, and a failure in this process may lead to human cancer.

Show MeSH
Related in: MedlinePlus