Asp/ASPM phospho-regulation throughout the cell cycle

Area of Science:

• Cell Biology
• Molecular Biology
• Genetics

Background:

• Asp/ASPM proteins are crucial for cell proliferation and spindle formation in mammals and Drosophila.
• Emerging evidence indicates Asp/ASPM proteins also have interphase roles, but their regulation across cell cycle phases remains unclear.

Purpose of the Study:

• To explore the regulation of Asp/ASPM proteins across different cell cycle phases.
• To investigate the potential role of cyclin-dependent kinases (CDK) in regulating Asp/ASPM functions.
• To hypothesize new regulatory mechanisms for Asp/ASPM in interphase and mitosis, and their dysregulation in disease.

Main Methods:

• Cross-species comparative analysis of Asp/ASPM protein sequences.
• Integration with existing cyclin-CDK literature.
• In silico structural predictions of human, mouse, and Drosophila Asp/ASPM proteins.
• Analysis of microcephaly patient truncation structures.

Main Results:

• Identified conserved N-terminal S/T-P phosphorylation "supershift" domains and putative cyclin-binding sites in Asp/ASPM proteins.
• Structural predictions suggest multisite phosphorylation can alter CH-domains and HEAT-motifs, influencing microtubule binding and protein aggregation.
• The arrangement of these motifs is critical, as highlighted by microcephaly patient structural data.

Conclusions:

• Asp/ASPM proteins are strong candidates for regulation by cyclin-CDKs, enabling distinct roles in interphase and mitosis.
• Multisite phosphorylation of the N-terminal domain may control Asp/ASPM's interaction with cellular components.
• Understanding Asp/ASPM regulation provides insights into microcephaly, cancer, and potential therapeutic strategies.