Cryo-EM of mammalian PA28αβ-iCP immunoproteasome reveals a distinct mechanism of proteasome activation by PA28αβ

Jinhuan Chen, Yifan Wang, Cong Xu, Kaijian Chen, Qiaoyu Zhao, Shutian Wang, Yue Yin, Chao Peng (), Zhanyu Ding () and Yao Cong ()
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Jinhuan Chen: Chinese Academy of Sciences
Yifan Wang: Chinese Academy of Sciences
Cong Xu: Chinese Academy of Sciences
Kaijian Chen: Chinese Academy of Sciences
Qiaoyu Zhao: Chinese Academy of Sciences
Shutian Wang: Chinese Academy of Sciences
Yue Yin: Shanghai Advanced Research Institute, CAS
Chao Peng: Shanghai Advanced Research Institute, CAS
Zhanyu Ding: Chinese Academy of Sciences
Yao Cong: Chinese Academy of Sciences

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract The proteasome activator PA28αβ affects MHC class I antigen presentation by associating with immunoproteasome core particles (iCPs). However, due to the lack of a mammalian PA28αβ-iCP structure, how PA28αβ regulates proteasome remains elusive. Here we present the complete architectures of the mammalian PA28αβ-iCP immunoproteasome and free iCP at near atomic-resolution by cryo-EM, and determine the spatial arrangement between PA28αβ and iCP through XL-MS. Our structures reveal a slight leaning of PA28αβ towards the α3-α4 side of iCP, disturbing the allosteric network of the gatekeeper α2/3/4 subunits, resulting in a partial open iCP gate. We find that the binding and activation mechanism of iCP by PA28αβ is distinct from those of constitutive CP by the homoheptameric TbPA26 or PfPA28. Our study sheds lights on the mechanism of enzymatic activity stimulation of immunoproteasome and suggests that PA28αβ-iCP has experienced profound remodeling during evolution to achieve its current level of function in immune response.

Date: 2021
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DOI: 10.1038/s41467-021-21028-3

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