Understanding Periperal Membrane Protein Interactions | BPS Thematic Meeting

Understanding Peripheral Membrane Protein Interactions: Structure, Dynamics, Function and Therapy

Poster Abstracts

17-POS Board 17 COMPUTATIONAL INVESTIGATION OF MEMBRANE-MODULATED DYNAMICS OF NON-VISUAL ARRESTINS Zeynep Nur Cinviz 1 ; Giulia Morra 2 ; Ozge Sensoy 1 ; 1 Istanbul Medipol University, Istanbul, Turkey 2 SCITEC CNR, Milano, Italy The discovery that non-visual arrestins, namely arrestin-2/3, initiate G protein-coupled receptor (GPCR) independent signaling, besides their primary role in GPCR desensitization, was a breakthrough. After then, they have been considered as promising targets in GPCR-focused drug discovery studies. Nevertheless, it is not trivial as the two members share high sequence similarity and a well-conserved structural fold hence posing selectivity problems. Moreover, the distal C-tail, which enables different functions of arrestin, is not resolved in experimental structures, limiting our understanding of how it mediates multifunctionality. Importantly, non visual arrestins shuttle between cytosol and membrane, yet molecular details that govern dynamics in these environments have remained elusive. We performed coarse-grained millisecond molecular dynamics simulations of non-visual arrestins with modeled full C-tail in water and at water/membrane using MARTINI forcefield with adjusted parameters to ensure that relevant biochemical, biophysical and structural experimental findings were represented. In backmapped trajectories, we showed that distal C-tail of arrestin-2 contacts more frequently with the gate and the finger loop, thus precluding their interactions with the polar core. Consequently, arrestin-2 sampled more positive interdomain rotation angle (IRA) with a mean of 0 degree, reminiscent of the basal state, whereas arrestin-3 sampled negative values in water. Notably, swapping of C-tails reversed the preference in IRA. Importantly, we also showed that first five residues contributed to stabilization of the basal state, as its truncation shifted IRA towards positive values, reminiscent of the intermediate state. We demonstrated that arrestin-2/3 spontaneously adsorbed to the membrane mediated by interactions between N-/C-edges of arrestin and phosphatidylinositol 4,5-bisphosphate (PIP 2 )s. Importantly, membrane stabilized more negative IRA for both isoforms. Interestingly, arrestin-2 preferred adsorption through C domain, whereas arrestin-3 displayed nearly equal preference towards N-and C-domain. Moreover, truncation of the distal C-tail changed it, and both isoforms preferred N-domain adsorption. The results provide molecular insights into dynamics of C-tail in water and at membrane, which can be used in future drug discovery studies focused on arrestin-isoform specific targeting for mediating various functions.

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