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| The molecular basis for phosphodependent substrate targeting and regulation of Plks by the Polo-box domain |
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| Author(s): Elia AEH, Rellos P, Haire LF, Chao JW, Ivins FJ, Hoepker K, Mohammad D, Cantley LC, Smerdon SJ, Yaffe MB |
| Source: CELL Volume: 115 Issue: 1 Pages: 83-95 Published: OCT 3 2003 |
| Times Cited: 193 References: 50 |
| Abstract: Polo-like kinases (Plks) perform crucial functions in cell-cycle progression and multiple stages of mitosis. Plks are characterized by a C-terminal noncatalytic region containing two tandem Polo boxes, termed the Polo-box domain (PBD), which has recently been implicated in phosphodependent substrate targeting. We show that the PBDs of human, Xenopus, and yeast Plks all recognize similar phosphoserine/threonine-containing motifs. The 1.9 Angstrom X-ray structure of a human Plk1 PBD-phosphopeptide complex shows that the Polo boxes each comprise beta(6)alpha structures that associate to form a 12-stranded beta sandwich domain. The phosphopeptide binds along a conserved, positively charged cleft located at the edge of the Polo-box interface. Mutations that specifically disrupt phosphodependent interactions abolish cell-cycle-dependent localization and provide compelling phenotypic evidence that PBD-phospholigand binding is necessary for proper mitotic progression. In addition, phosphopeptide binding to the PBD stimulates kinase activity in full-length Plk1, suggesting a conformational switching mechanism for Plk regulation and a dual functionality for the PBD. |
| Document Type: Article |
| Language: English |
| Reprint Address: Smerdon, SJ (reprint author), Natl Inst Med Res, Div Prot Struct, London NW7 1AA, England |
Addresses:
1. Natl Inst Med Res, Div Prot Struct, London NW7 1AA, England
2. MIT, Ctr Canc Res, Dept Biol, Cambridge, MA 02139 USA
3. Harvard Univ, Beth Israel Deaconess Hosp, Sch Med, Dept Cell Biol,Div Signal Transduct, Boston, MA 02215 USA |
| Publisher: CELL PRESS, 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA |
| Subject Category: Biochemistry & Molecular Biology; Cell Biology |
| IDS Number: 730ED |
| ISSN: 0092-8674 |
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