[Seminar] Quality Control of Protein Complex Assembly
Eszter Zavodszky
| When |
14 Apr, 2025
from
02:00 pm to 03:00 pm |
|---|---|
| Where | ITQB NOVA Auditorium |
| Contact Name | Pedro Domingos |
| Contact Email | domingp@itqb.unl.pt |
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Title: Quality Control of Protein Complex Assembly
Speaker: Eszter Zavodszky
From: MRC Laboratory of Molecular Biology, Cambridge, UK
Abstract: Approximately half of all proteins encoded by the human genome form multi-protein complexes. The inherent noisiness of transcription and translation leads to imbalances in the synthesis of their subunits. Cellular stress and various disease states – most notably cancer – can exacerbate subunit imbalances due to aneuploidy and dysregulated gene expression. Although it has long been appreciated that unassembled subunits and intermediates are degraded to prevent their potentially toxic accumulation, the requisite quality control pathways are only beginning to emerge. We have recently found that unassembled subunits of several abundant cytosolic complexes, including the proteasome and chaperonin, are initially mono-ubiquitinated by giant ubiquitin ligases such as HERC1 and HERC2. Unlike previously described quality control pathways relying on degrons or exposed hydrophobic regions in misfolded proteins, these ligases use adapters to distinguish unassembled, but otherwise folded, substrates. An additional commitment step is required for degradation, mediated by the UBR4-KCMF1 ubiquitin ligase complex, which selectively modifies a variety of mono-ubiquitinated orphans with poly-ubiquitin. We therefore propose that an assortment of priming ligases catalyse the initial recognition and mono-ubiquitination of unassembled proteins, and these quality control pathways converge on the chain-elongating UBR4-KCMF1 ligase complex. Such a convergence point may explain why aneuploid cancer cells are especially vulnerable to loss of UBR4 and KCMF1.
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Goal 3. Good health and well-being
