2mpt
From Proteopedia
WW3 domain of Nedd4L in complex with its HECT domain PY motif
Structural highlights
Function[NED4L_HUMAN] E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Inhibits TGF-beta signaling by triggering SMAD2 and TGFBR1 ubiquitination and proteasome-dependent degradation. Promotes ubiquitination and internalization of various plasma membrane channels such as ENaC, Nav1.2, Nav1.3, Nav1.5, Nav1.7, Nav1.8, Kv1.3, EAAT1 or CLC5. Promotes ubiquitination and degradation of SGK1 and TNK2.[1] [2] [3] [4] [5] [6] [7] Publication Abstract from PubMedWe investigated the mechanisms of activation and degradation of the E3 ubiquitin ligase Nedd4L combining the available biochemical information with complementary biophysical techniques. Using nuclear magnetic resonance spectroscopy, we identified that the C2 domain binds Ca(2+) and inositol 1,4,5-trisphosphate (IP3) using the same interface that is used to interact with the HECT domain. Thus, we propose that the transition from the closed to the active form is regulated by a competition of IP3 and Ca(2+) with the HECT domain for binding to the C2 domain. We performed relaxation experiments and molecular dynamic simulations to determine the flexibility of the HECT structure and observed that its conserved PY motif can become solvent-exposed when the unfolding process is initiated. The structure of the WW3 domain bound to the HECT-PY site reveals the details of this interaction, suggesting a possible auto-ubquitination mechanism using two molecules, a partially unfolded one and a fully functional Nedd4L counterpart. Structural Basis of the Activation and Degradation Mechanisms of the E3 Ubiquitin Ligase Nedd4L.,Escobedo A, Gomes T, Aragon E, Martin-Malpartida P, Ruiz L, Macias MJ Structure. 2014 Oct 7;22(10):1446-57. doi: 10.1016/j.str.2014.08.016. PMID:25295397[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Aragon, E | Escobedo, A | Gomes, T | Macias, M J | Martin-Malpartida, P | Ruiz, L | Auto-ubiquitination | Hect | Ligase | Nedd4 2 | Nedd4l | Proteasomal degradation | Py | Ubiquitin ligase | Ww | Ww3
