The midnolin-proteasome pathway catches proteins for ubiquitination-independent degradation
Authors/Creators
- 1. Harvard Medical School
- 2. Harvard University
Description
Cells use ubiquitin to mark proteins for proteasomal degradation. While the proteasome also eliminates proteins that are not modified by ubiquitin, how this occurs mechanistically is unclear. We show here that midnolin promotes the destruction of many nuclear proteins including transcription factors encoded by the immediate-early-genes. Diverse environmental cues induce midnolin and its overexpression is sufficient to cause the degradation of its targets by a mechanism, which, remarkably, does not require ubiquitination. Instead, midnolin associates with the proteasome via an alpha-helix, employs its Catch-domain to bind a region within substrates that adopts a beta-strand conformation, and uses a ubiquitin-like-domain to promote substrate destruction. Thus, midnolin contains three regions that function in concert to target a large set of nuclear proteins to the proteasome for degradation.
Notes
PDB files for AlphaFold multimer predictions can be opened with softwares such as PyMOL and ChimeraX.
Funding provided by: Damon Runyon Cancer Research Foundation
Crossref Funder Registry ID: http://dx.doi.org/10.13039/100001021
Award Number: DRG-2469-22
Funding provided by: National Science Foundation
Crossref Funder Registry ID: http://dx.doi.org/10.13039/100000001
Award Number:
Funding provided by: National Institutes of Health
Crossref Funder Registry ID: http://dx.doi.org/10.13039/100000002
Award Number: R01 NS115965
Funding provided by: National Institutes of Health
Crossref Funder Registry ID: http://dx.doi.org/10.13039/100000002
Award Number: AG11085
Funding provided by: National Institutes of Health
Crossref Funder Registry ID: http://dx.doi.org/10.13039/100000002
Award Number: T32 HG002295
Funding provided by: Howard Hughes Medical Institute
Crossref Funder Registry ID: http://dx.doi.org/10.13039/100000011
Award Number:
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DataS1_Raw_DNA_Seq_EGR1_and_FosB_GW_CRISPR_Cas9_Screens.zip
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