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ch-TOG与TACC3之间相互作用的结构表征及抑制

Structural characterization and inhibition of the interaction between ch-TOG and TACC3.

作者信息

Shelford James, Burgess Selena G, Rostkova Elena, Richards Mark W, Larocque Gabrielle, Sampson Josephina, Tiede Christian, Fielding Alistair J, Daviter Tina, Tomlinson Darren C, Calabrese Antonio N, Pfuhl Mark, Bayliss Richard, Royle Stephen J

机构信息

Centre for Mechanochemical Cell Biology, Warwick Medical School, University of Warwick, Coventry, UK.

School of Molecular and Cellular Biology, Astbury Centre for Structural Biology, Faculty of Biological Sciences, University of Leeds , Leeds, UK.

出版信息

J Cell Biol. 2025 Jun 2;224(6). doi: 10.1083/jcb.202407002. Epub 2025 Mar 19.

DOI:10.1083/jcb.202407002
PMID:40105698
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11921806/
Abstract

The mitotic spindle is a bipolar array of microtubules, radiating from the poles which each contain a centrosome, embedded in pericentriolar material. Two proteins, ch-TOG and TACC3, have multiple functions at the mitotic spindle due to operating either alone, together, or in complex with other proteins. To distinguish these activities, we need new molecular tools to dissect their function. Here, we present the structure of the α-helical bundle domain of ch-TOG that mediates its interaction with TACC3 and a structural model describing the interaction, supported by biophysical and biochemical data. We have isolated Affimer tools to precisely target the ch-TOG-binding site on TACC3 in live cells, which displace ch-TOG without affecting the spindle localization of other protein complex components. Inhibition of the TACC3-ch-TOG interaction led unexpectedly to fragmentation of the pericentriolar material in metaphase cells and delayed mitotic progression, uncovering a novel role of TACC3-ch-TOG in maintaining pericentriolar material integrity during mitosis to ensure timely cell division.

摘要

有丝分裂纺锤体是由微管组成的双极阵列，从每个包含一个中心体的两极辐射而出，中心体嵌入中心粒周围物质中。两种蛋白质，即ch-TOG和TACC3，由于单独发挥作用、共同发挥作用或与其他蛋白质形成复合物，因而在有丝分裂纺锤体中具有多种功能。为了区分这些活性，我们需要新的分子工具来剖析它们的功能。在此，我们展示了ch-TOG的α-螺旋束结构域的结构，该结构域介导其与TACC3的相互作用，并给出了一个描述这种相互作用的结构模型，该模型得到了生物物理和生化数据的支持。我们分离出了Affimer工具，以精确靶向活细胞中TACC3上的ch-TOG结合位点，该工具可取代ch-TOG，而不影响其他蛋白质复合物组分在纺锤体上的定位。对TACC3-ch-TOG相互作用的抑制意外地导致中期细胞的中心粒周围物质碎片化，并延迟有丝分裂进程，揭示了TACC3-ch-TOG在有丝分裂期间维持中心粒周围物质完整性以确保细胞及时分裂方面的新作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96a1/11921806/61de4a1c4800/jcb_202407002_fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96a1/11921806/dc454e039601/jcb_202407002_figs1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96a1/11921806/8c70cf6130a3/jcb_202407002_fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96a1/11921806/045ddfb52952/jcb_202407002_figs2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96a1/11921806/ea46097904a2/jcb_202407002_fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96a1/11921806/46e0fa9bc4b3/jcb_202407002_fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96a1/11921806/3d94f853fe6f/jcb_202407002_figs3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96a1/11921806/182b8f556d03/jcb_202407002_fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96a1/11921806/9c579a703523/jcb_202407002_figs4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96a1/11921806/fd2b9d2db116/jcb_202407002_fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96a1/11921806/38369b8ae9bd/jcb_202407002_figs5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96a1/11921806/c5fd2450d8ce/jcb_202407002_fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96a1/11921806/bea2bc1ff616/jcb_202407002_fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96a1/11921806/61de4a1c4800/jcb_202407002_fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96a1/11921806/dc454e039601/jcb_202407002_figs1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96a1/11921806/8c70cf6130a3/jcb_202407002_fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96a1/11921806/045ddfb52952/jcb_202407002_figs2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96a1/11921806/ea46097904a2/jcb_202407002_fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96a1/11921806/46e0fa9bc4b3/jcb_202407002_fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96a1/11921806/3d94f853fe6f/jcb_202407002_figs3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96a1/11921806/182b8f556d03/jcb_202407002_fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96a1/11921806/9c579a703523/jcb_202407002_figs4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96a1/11921806/fd2b9d2db116/jcb_202407002_fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96a1/11921806/38369b8ae9bd/jcb_202407002_figs5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96a1/11921806/c5fd2450d8ce/jcb_202407002_fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96a1/11921806/bea2bc1ff616/jcb_202407002_fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96a1/11921806/61de4a1c4800/jcb_202407002_fig8.jpg

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