Structural and functional analyses of minimal phosphopeptides targeting the polo-box domain of polo-like kinase 1.
Polo-like kinase-1 (Plk1) has a pivotal role in cell proliferation and is considered a potential target for anticancer therapy. The noncatalytic polo-box domain (PBD) of Plk1 forms a phosphoepitope binding module for protein-protein interaction. Here, we report the identification of minimal phosphopeptides that specifically interact with the PBD of human PLK1, but not those of the closely related PLK2 and PLK3. Comparative binding studies and analyses of crystal structures of the PLK1 PBD in complex with the minimal phosphopeptides revealed that the C-terminal SpT dipeptide functions as a high-affinity anchor, whereas the N-terminal residues are crucial for providing specificity and affinity to the interaction. Inhibition of the PLK1 PBD by phosphothreonine mimetic peptides was sufficient to induce mitotic arrest and apoptotic cell death. The mode of interaction between the minimal peptide and PBD may provide a template for designing therapeutic agents that target PLK1.
Yun
Sang-Moon
SM
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Moulaei
Tinoush
T
Lim
Dan
D
Bang
Jeong K
JK
Park
Jung-Eun
JE
Shenoy
Shilpa R
SR
Liu
Fa
F
Kang
Young H
YH
Liao
Chenzhong
C
Soung
Nak-Kyun
NK
Lee
Sunhee
S
Yoon
Do-Young
DY
Lim
Yoongho
Y
Lee
Dong-Hee
DH
Otaka
Akira
A
Appella
Ettore
E
McMahon
James B
JB
Nicklaus
Marc C
MC
Burke
Terrence R
TR
Yaffe
Michael B
MB
Wlodawer
Alexander
A
Lee
Kyung S
KS
D000595:Amino Acid Sequence; D001665:Binding Sites; D001667:Binding, Competitive; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010748:Phosphopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013816:Thermodynamics; D013912:Threonine / Q000378:metabolism; D000097869:Polo-Like Kinase 1
D018797:Cell Cycle Proteins; D010748:Phosphopeptides; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D013912:Threonine; D000097869:Polo-Like Kinase 1