Synergistic recruitment of UbcH7~Ub and phosphorylated Ubl domain triggers parkin activation

We present a model of an E2~Ub conjugate bound to the phospho-ubiquitin-loaded C-terminus of parkin, derived from NMR chemical shift perturbation experiments. We show the UbcH7~Ub conjugate binds in the open state whereby conjugated ubiquitin binds to the RING1/IBR interface. Further, NMR and mass spectrometry experiments indicate the RING0/RING2 interface is re-modelled, remote from the E2 binding site, and this alters the reactivity of the RING2(Rcat) catalytic cysteine, needed for ubiquitin transfer. Our experiments provide evidence that parkin phosphorylation and E2~Ub recruitment act synergistically to enhance a weak interaction of the pUbl domain with the RING0 domain and rearrange the location of the RING2(Rcat) domain to drive parkin activity.

Source: EMBO Journal - December 3, 2018 Category: Molecular Biology Authors: Condos, T. E., Dunkerley, K. M., Freeman, E. A., Barber, K. R., Aguirre, J. D., Chaugule, V. K., Xiao, Y., Konermann, L., Walden, H., Shaw, G. S. Tags: Post-translational Modifications, Proteolysis & Proteomics, Structural Biology Articles Source Type: research