Abstract
U24 is a protein found in both roseoloviruses Human Herpes Virus type 6 and 7 (HHV-6 and HHV-7), with an N-terminus that is rich in prolines (PY motif in both HHV-6A and 7; PxxP motif in HHV-6A). Previous work has shown that the interaction between U24 and WW domains is important for endocytic recycling of T-cell receptors, but a cognate ligand was never identified. In this contribution, data was obtained from pull-downs, ITC, NMR and molecular dynamics simulations to show that a specific interaction exists between U24 and Nedd4 WW domains. ITC experiments were also carried out for U24 from HHV-6A phosphorylated at Thr6 (pU24-6A) and a peptide containing the PY motif from Nogo-A, a protein implicated in both the initial inflammatory and the neurodegenerative phases of multiple sclerosis (MS). The results suggest that phosphorylation of U24 from HHV-6A may be crucial for its potential role in MS.
Highlights
In oligodendrocyte differentiation and myelination is neurite outgrowth inhibitor, Nogo-A, which has a PY motif (Fig. 1a)
In order to compare with previously reported results[35], experiments were carried out on four relevant WW domains: the second and the third WW domain of rat Nedd[4], and the pair of third WW domains from human Nedd[4]
The WW3 domains are indicated with a star because this type of WW domain is missing in rat and mouse Nedd[436,37]
Summary
In oligodendrocyte differentiation and myelination is neurite outgrowth inhibitor, Nogo-A, which has a PY motif (Fig. 1a). Nogo-A expression is tightly regulated by Praja[2], a member of the RING family of E3 ubiquitin ligases[24]. Sodium channels have been found to be more frequently associated with MS lesions[25,26,27] Sodium channels, such as epithelial sodium channel (ENaC), undergo endocytosis through a clathrin-dependent pathway, which is regulated by Nedd[4] family E3 ubiquitin ligase[28]. We have focussed our studies on human Nedd[4] WW domains (hNedd[4] and hNedd4L, Fig. 1b) given their relevance in the CNS, noted above. Some of the data obtained is compared to the binding interaction between the PY motif of Nogo-A and hNedd4L-WW3*, determined here
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