Microtubule minus-end regulation at spindle poles by an ASPM-katanin complex

Nat Cell Biol. 2017 May;19(5):480-492. doi: 10.1038/ncb3511. Epub 2017 Apr 24.

Abstract

ASPM (known as Asp in fly and ASPM-1 in worm) is a microcephaly-associated protein family that regulates spindle architecture, but the underlying mechanism is poorly understood. Here, we show that ASPM forms a complex with another protein linked to microcephaly, the microtubule-severing ATPase katanin. ASPM and katanin localize to spindle poles in a mutually dependent manner and regulate spindle flux. X-ray crystallography revealed that the heterodimer formed by the N- and C-terminal domains of the katanin subunits p60 and p80, respectively, binds conserved motifs in ASPM. Reconstitution experiments demonstrated that ASPM autonomously tracks growing microtubule minus ends and inhibits their growth, while katanin decorates and bends both ends of dynamic microtubules and potentiates the minus-end blocking activity of ASPM. ASPM also binds along microtubules, recruits katanin and promotes katanin-mediated severing of dynamic microtubules. We propose that the ASPM-katanin complex controls microtubule disassembly at spindle poles and that misregulation of this process can lead to microcephaly.

Publication types

  • Video-Audio Media

MeSH terms

  • Adenosine Triphosphatases / chemistry
  • Adenosine Triphosphatases / genetics
  • Adenosine Triphosphatases / metabolism*
  • CRISPR-Cas Systems
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Katanin
  • Microcephaly / genetics
  • Microcephaly / metabolism*
  • Microcephaly / pathology
  • Microtubules / enzymology*
  • Microtubules / genetics
  • Microtubules / pathology
  • Models, Molecular
  • Mutation
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Protein Binding
  • Protein Conformation
  • Protein Interaction Domains and Motifs
  • Signal Transduction
  • Spindle Poles / enzymology*
  • Spindle Poles / genetics
  • Spindle Poles / pathology
  • Structure-Activity Relationship
  • Time Factors
  • Transfection

Substances

  • ASPM protein, human
  • Nerve Tissue Proteins
  • Adenosine Triphosphatases
  • katanin p80, human
  • KATNA1 protein, human
  • Katanin