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May 21st, 2025
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University of California, Los Angeles
biochemistry
biorxiv

Structural basis for L-isoaspartyl-containing protein recognition by the PCMTD1 cullin-RING E3 ubiquitin ligase

Pang, E. Z.Open in Google Scholar•Zhao, B.Open in Google Scholar•Flowers, C.Open in Google Scholar•Oroudjeva, E.Open in Google Scholar•Winter, J. B.Open in Google Scholar•Pandey, V.Open in Google Scholar•Sawaya, M. R.Open in Google Scholar•Wohlschlegel, J.Open in Google Scholar•Loo, J. A.Open in Google Scholar•Rodriguez, J. A.Open in Google Scholaret al.

A major type of spontaneous protein damage that accumulates with age is the formation of kinked polypeptide chains with L-isoaspartyl residues. Mitigating this damage is necessary for maintaining proteome stability and prolonging organismal survival. While repair through methylation by PCMT1 has been previously shown to suppress L-isoaspartyl accumulation, we provide an additional mechanism for L-isoaspartyl maintenance through PCMTD1, a cullin-RING ligase (CRL). We combined cryo-EM, native mass spectrometry, and biochemical assays to provide insight on how the assembly and architecture of PCMTD1 in the context of a CRL complex fulfils this alternative mechanism. We show that the PCMTD1 CRL complex specifically binds L-isoaspartyl residues when bound to AdoMet. This work provides evidence for a growing class of E3 ubiquitin ligases that recognize spontaneous covalent modifications as potential substrates for ubiquitylation and subsequent proteasomal degradation.

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