Selective targeting of non-centrosomal AURKA functions through use of a targeted protein degradation tool

Faculty Science Year: 2021
Type of Publication: ZU Hosted Pages:
Authors:
Journal: communications biology Nature Volume:
Keywords : Selective targeting , non-centrosomal AURKA functions through    
Abstract:
Targeted protein degradation tools are becoming a new therapeutic modality, allowing small molecule ligands to be reformulated as heterobifunctional molecules (PROteolysis Targeting Chimeras, PROTACs) that recruit ubiquitin ligases to targets of interest, leading to ubiquitination and destruction of the targets. Several PROTACs against targets of clinical interest have been described, but detailed descriptions of the cell biology modulated by PROTACs are missing from the literature. Here we describe the functional characterization of a PROTAC derived from AURKA inhibitor MLN8237 (alisertib). We demonstrate efficient and specific destruction of both endogenous and overexpressed AURKA by Cereblon-directed PROTACs. At the subcellular level, we find differential targeting of AURKA on the mitotic spindle compared to centrosomes. The phenotypic consequences of PROTAC treatment are therefore distinct from those mediated by alisertib, and in mitotic cells differentially regulate centrosome- and chromatin- based microtubule spindle assembly pathways. In interphase cells PROTAC-mediated clearance of non-centrosomal AURKA modulates the cytoplasmic role played by AURKA in mitochondrial dynamics, whilst the centrosomal pool is refractory to PROTAC-mediated clearance. Our results point to differential sensitivity of subcellular pools of substrate, governed by substrate conformation or localization-dependent accessibility to PROTAC action, a phenomenon not previously described for this new class of degrader compounds.
   
     
 
       

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  • Ahmed Mohamed Abdelbaky Abedulaal, "Constitutive regulation of mitochondrial morphology by Aurora A kinase depends on a predicted cryptic targeting sequence at the N-terminus", Royal Society_Open Biology 8(6):170272Royal Society, 2018 More
  • Ahmed Mohamed Abdelbaky Abedulaal, "AURKA destruction is decoupled from its activity at mitotic exit but essential to suppress interphase activity", The Company of Biologists, 2020 More
  • Ahmed Mohamed Abdelbaky Abedulaal, "Selective targeting of non-centrosomal AURKA functions through use of a targeted protein degradation tool", Nature, 2021 More
  • Ahmed Mohamed Abdelbaky Abedulaal, "Revisiting degron motifs in human AURKA required for its targeting by APC/C-FZR1", EMBO Press, Rockefeller University Press and Cold Spring Harbor Laboratory Press, 2022 More

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