title: Structural basis for recognition of Emi2 by Polo-like kinase 1 and development of peptidomimetics blocking oocyte maturation and fertilization.
abstract: In a mammalian oocyte, completion of meiosis is suspended until fertilization by a sperm, and the cell cycle is arrested by a biochemical activity called cytostatic factor (CSF). Emi2 is one of the CSFs, and it maintains the protein level of maturation promoting factor (MPF) by inhibiting ubiquitin ligase anaphase promoting complex/cyclosome (APC/C). Degradation of Emi2 via ubiquitin-mediated proteolysis after fertilization requires phosphorylation by Polo-like kinase 1 (Plk1). Therefore, recognition and phosphorylation of Emi2 by Plk1 are crucial steps for cell cycle resumption, but the binding mode of Emi2 and Plk1 is poorly understood. Using biochemical assays and X-ray crystallography, we found that two phosphorylated threonines (Thr(152) and Thr(176)) in Emi2 are each responsible for the recruitment of one Plk1 molecule by binding to its C-terminal polo box domain (PBD). We also found that meiotic maturation and meiosis resumption via parthenogenetic activation were impaired when Emi2 interaction with Plk1-PBD was blocked by a peptidomimetic called 103-8. Because of the inherent promiscuity of kinase inhibitors, our results suggest that targeting PBD of Plk1 may be an effective strategy for the development of novel and specific contraceptive agents that block oocyte maturation and/or fertilization.
authors.affiliation: Department of Animal Sciences, Chungbuk National University, Republic of Korea.
authors.forename: Jia-Lin
authors.initials: JL
authors.lastname: Jia
authors.affiliation: Department of Animal Sciences, Chungbuk National University, Republic of Korea.
authors.forename: Young-Hyun
authors.initials: YH
authors.lastname: Han
authors.affiliation: Department of Animal Sciences, Chungbuk National University, Republic of Korea.
authors.forename: Hak-Cheol
authors.initials: HC
authors.lastname: Kim
authors.affiliation: Division of Magnetic Resonance, Korea Basic Science Institute, Ochang, Korea.
authors.forename: Mija
authors.initials: M
authors.lastname: Ahn
authors.affiliation: Department of Animal Sciences, Chungbuk National University, Republic of Korea.
authors.forename: Jeong-Woo
authors.initials: JW
authors.lastname: Kwon
authors.affiliation: Department of Animal Sciences, Chungbuk National University, Republic of Korea.
authors.forename: Yibo
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Department of Animal Sciences, Chungbuk National University, Republic of Korea.
authors.forename: Pethaiah
authors.initials: P
authors.lastname: Gunasekaran
authors.affiliation: College of Pharmacy, Chungbuk National University, Republic of Korea.
authors.forename: Soo-Jae
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: National Cancer Institute, National Institute of Health, Rockville, Maryland, United States.
authors.forename: Kyung S
authors.initials: KS
authors.lastname: Lee
authors.affiliation: Division of Magnetic Resonance, Korea Basic Science Institute, Ochang, Korea.
authors.forename: Jeong
authors.initials: J
authors.lastname: Kyu Bang
authors.affiliation: Department of Animal Sciences, Chungbuk National University, Republic of Korea.
authors.forename: Nam-Hyung
authors.initials: NH
authors.lastname: Kim
authors.affiliation: Department of Animal Sciences, Chungbuk National University, Republic of Korea.
authors.forename: Suk
authors.initials: S
authors.lastname: Namgoong
mesh_terms: D000818:Animals; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000737:chemistry* / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D044783:F-Box Proteins / Q000737:chemistry* / Q000378:metabolism; D005306:Fertilization / Q000187:drug effects; D008540:Meiosis / Q000187:drug effects; D000090204:Mesothelin; D051379:Mice; D008958:Models, Molecular; D009865:Oocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D057786:Peptidomimetics / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000378:metabolism; D059748:Proteolysis; D011518:Proto-Oncogene Proteins / Q000737:chemistry* / Q000378:metabolism; D008941:Spindle Apparatus / Q000378:metabolism; D013329:Structure-Activity Relationship; D014981:Xenopus; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000090204:Mesothelin; D057786:Peptidomimetics; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1; C509434:Emi2 protein, mouse; C000715528:Msln protein, mouse