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Instruments / Technical Area	Publication Details	Published	Actions
I04-1-Macromolecular Crystallography (fixed wavelength)	Stabilization of the retromer complex: analysis of novel binding sites of bis-1,3-phenyl guanylhydrazone 2a to the VPS29/VPS35 interface Elisa Fagnani , Francesco Boni , Pierfausto Seneci , Davide Gornati , Luca Muzio , Eloise Mastrangelo , Mario Milani Computational And Structural Biotechnology Journal 1–2 DOI: 10.1016/j.csbj.2024.02.026 Open Access Show Abstract ▼ Abstract: The stabilization of the retromer protein complex can be effective in the treatment of different neurological disorders. Following the identification of bis-1,3-phenyl guanylhydrazone 2a as an effective new compound for the treatment of amyotrophic lateral sclerosis, in this work we analyze the possible binding sites of this molecule to the VPS35/VPS29 dimer of the retromer complex. Our results show that the affinity for different sites of the protein assembly depends on compound charge and therefore slight changes in the cell microenvironment could promote different binding states. Finally, we describe a novel binding site located in a deep cleft between VPS29 and VPS35 that should be further explored to select novel molecular chaperones for the stabilization of the retromer complex.	Mar 2024
I04-Macromolecular Crystallography	A novel hotspot of gelsolin instability triggers an alternative mechanism of amyloid aggregation Michela Bollati , Luisa Diomede , Toni Giorgino , Carmina Natale , Elisa Fagnani , Irene Boniardi , Alberto Barbiroli , Rebecca Alemani , Marten Beeg , Marco Gobbi , Ana Fakin , Eloise Mastrangelo , Mario Milani , Gianluca Presciuttini , Edi Gabellieri , Patrizia Cioni , Matteo De Rosa Computational And Structural Biotechnology Journal 281 DOI: 10.1016/j.csbj.2021.11.025 Diamond Proposal Number(s): [20221] Open Access Show Abstract ▼ Abstract: Gelsolin comprises six homologous domains, named G1 to G6. Single point substitutions in this protein are responsible for AGel amyloidosis, a hereditary disease causing progressive corneal lattice dystrophy, cutis laxa, and polyneuropathy. Although several different amyloidogenic variants of gelsolin have been identified, only the most common mutants present in the G2 domain have been thoroughly characterized, leading to clarification of the functional mechanism. The molecular events underlying the pathological aggregation of 3 recently identified mutations, namely A551P, E553K and M517R, all localized at the interface between G4 and G5, are here explored for the first time. . Structural studies point to destabilization of the interface between G4 and G5 due to three structural determinants: β-strand breaking, steric hindrance and/or charge repulsion, all implying impairment of interdomain contacts. Such rearrangements decrease the temperature and pressure stability of gelsolin but do not alter its susceptibility to furin cleavage, the first event in the canonical aggregation pathway. These variants also have a greater tendency to aggregate in the unproteolysed forms and exhibit higher proteotoxicity in a C. elegans-based assay. Our data suggest that aggregation of G4G5 variants follows an alternative, likely proteolysis-independent, pathway.	Nov 2021

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