Nutrient copper signaling promotes protein turnover by allosteric activation of ubiquitin E2D conjugases

• DOI: 10.1101/2021.02.15.431211
• Publication Date: 2021-02-16T21:20:24Z
• Authors: C.M. Opazo; A. Lotan; Z. Xiao; B. Zhang; M.A. Greenough; C.M. Lim; H. Trytell; A. Ramírez; A.A. Ukuwela; C.H. Mawal; J. McKenna; D.N. Saunders; R. Burke; P.R. Gooley; A.I. Bush
• Keywords: 0303 health sciences; 03 medical and health sciences

SUMMARY Nutrient copper supply is critical for cell growth and differentiation, its disturbance associated with major pathologies including cancer neurodegeneration. Although increasing bioavailability in late Precambrian facilitated emergence of novel cuproproteins, their intricate regulation by this essential trace element remains largely cryptic. We found that subtle rises cellular strikingly increase polyubiquitination accelerate protein degradation within 30 minutes numerous mammalian lines. track surprising observation to allostery induced the UBE2D ubiquitin conjugase clade through a conserved CXXXC sub-femtomolar-affinity Cu + binding motif. Thus, physiologic fluctuation cytoplasmic coupled prompt targets, p53. In Drosophila harboring larval-lethal knockdown nearly identical fly orthologue UbcD1, complementation human UBE2D2 restored near-normal development, but mutation motif profoundly disrupted organogenesis. emerges as trophic allosteric modulator activity structural whose evolution coincides animal multicellularity. One Sentence Summary Modulation nutrient impacts turnover morphogenesis E2D conjugases. Hilights differentiation The conjugases contains Allosteric activation markedly accelerates This sensor couples fluctuations rate p53 metazoan signaling mechanism drosophila Brief Conserved links morphogenesis. Abstract Figure Graphical