Asp/ASPM phospho-regulation throughout the cell cycle.

Abstract

In mammals and Drosophila melanogaster, Asp/ASPM proteins contribute to cell proliferation and spindle formation. Recent evidence also suggests interphase roles for Asp/ASPM proteins, but little is known about the regulation allowing distinct roles in different cell cycle phases. In this review, we consider a cross-species comparison of Asp/ASPM protein sequences in light of cyclin-CDK literature, and suggest Asp/ASPM proteins to be prime candidates for cyclin-CDK regulation. Conserved regulatory features include an N-terminal proline directed serine/threonine (S/T-P) "supershift" phosphorylation domain common to proteins with bistable interphase and mitotic roles, as well as putative cyclin-binding sites positioned to allow multisite phosphorylation by cyclin-CDK complexes. Human, mouse, and Drosophila Asp/ASPM protein structural predictions show that multisite phosphorylation of the N-term supershift domain could alter the availability of CH-domains and HEAT-motifs, which can contribute to microtubule binding and protein aggregation likely required for spindle formation. Structural predictions of the smallest reported microcephaly patient truncation also emphasize the importance of the arrangement of these motifs. We position this in silico analysis within recent literature to build new hypotheses for Asp/ASPM regulation in interphase and mitosis, as well as de-regulation in microcephaly and cancer. We also highlight the utility of comparing structural/functional differences between human ASPM and Drosophila Asp to gain further insight.