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Degron mimicry modulates selective substrate recruitment by CTLH E3 supramolecular assembly

ABSTRACT: Selective protein degradation by the Ubiquitin Proteasome System (UPS) is largely regulated by multi-subunit E3 ligase complexes commonly utilizing interchangeable degron-receptors to target a plethora of different substrates. Here, we identified nicotinamide/nicotinacid-mononlucletide-adenylyltransferase 1 (NMNAT1) as a cognate substrate of CTLH E3 complex, and report structural, biochemical, and cell biology studies revealing a mechanism of a degron-selective receptor function of the inherent non-interchangeable CTLH supramolecular assembly subunit WDR26, tailored to avidly bind and target NMNAT1 hexamer. Importantly, WDR26 receptor is gated by a degron-mimicry of the N-terminus of the CTLH subunit YPEL5 that corrupts ubiquitin targeting of NMNAT1. Cellular YPEL5 depletion is sufficient to destabilize NMNAT1 and to attenuate cytotoxicity of the NMNAT1-activated anticancer drug Tiazofurin. Cumulatively, we propose a regulatory concept of degron selection and binding by the WDR26-CTLH supramolecular assembly, potentially applying to substrates other than NMNAT1.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Mario Oroshi

LAB HEAD: Matthias Mann

PROVIDER: PXD044126 | Pride | 2024-05-16

REPOSITORIES: Pride

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			Action	DRS
	20201207_EXPL4_OzKa_SA_Arno_HEK293_TUBE_10.raw	Raw
	20201207_EXPL4_OzKa_SA_Arno_HEK293_TUBE_11.raw	Raw
	20201207_EXPL4_OzKa_SA_Arno_HEK293_TUBE_12.raw	Raw
	20201207_EXPL4_OzKa_SA_Arno_HEK293_TUBE_13.raw	Raw
	20201207_EXPL4_OzKa_SA_Arno_HEK293_TUBE_14.raw	Raw

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