Dynactin helps target Polo-like kinase 1 to kinetochores via its left-handed beta-helical p27 subunit.

Department of Biology, Johns Hopkins University, Baltimore, MD, USA.
Dynactin is a protein complex required for the in vivo function of cytoplasmic dynein, a microtubule (MT)-based motor. Dynactin binds both dynein and MTs via its p150(Glued) subunit, but little is known about the 'pointed-end complex' that includes the protein subunits Arp11, p62 and the p27/p25 heterodimer. Here, we show that the p27/p25 heterodimer undergoes mitotic phosphorylation by cyclin-dependent kinase 1 (Cdk1) at a single site, p27 Thr186, to generate an anchoring site for polo-like kinase 1 (Plk1) at kinetochores. Removal of p27/p25 from dynactin results in reduced levels of Plk1 and its phosphorylated substrates at kinetochores in prometaphase, which correlates with aberrant kinetochore-MT interactions, improper chromosome alignment and abbreviated mitosis. To investigate the structural implications of p27 phosphorylation, we determined the structure of human p27. This revealed an unusual left-handed β-helix domain, with the phosphorylation site located within a disordered, C-terminal segment. We conclude that dynactin plays a previously undescribed regulatory role in the spindle assembly checkpoint by recruiting Plk1 to kinetochores and facilitating phosphorylation of important downstream targets.
Mesh Terms:
Animals, Cattle, Cell Cycle Proteins, Cell Line, Chick Embryo, Humans, Kinetochores, Mice, Microtubule-Associated Proteins, Microtubules, Mitotic Spindle Apparatus, Phosphorylation, Protein Structure, Tertiary, Protein Subunits, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins
EMBO J. Apr. 03, 2013; 32(7);1023-35 [PUBMED:23455152]
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