Marcello Miceli

and 5 more

Despite the ubiquity of Membrane Occupation Recognition Nexus (MORN) motifs across diverse species in both eukaryotic and prokaryotic organisms, these protein domains remain poorly characterized. Their significance is underscored in the context of the Alsin protein, implicated in the debilitating condition known as Infantile-onset Ascending Hereditary Spastic Paralysis (IAHSP). Studies have proposed that mutations within the Alsin MORN domain disrupt proper protein assembly, precluding the formation of the requisite tetrameric configuration essential for the protein’s inherent biological activity. However, a comprehensive understanding of the relationship between the biological functions of Alsin and its three-dimensional molecular structure is hindered by the lack of available experimental structures. In this study, by comparing experimentally resolved MORN domains, we predicted a three-dimensional structure for the putative MORN of Alsin. Furthermore, inspired by experimental pieces of evidence from previous studies, we employed the developed models to predict and investigate two homo-dimeric assemblies, characterising their stability. This study’s insights into the three-dimensional structure of the Alsin MORN domain and the stability dynamics of its homo-dimeric assemblies suggest an antiparallel linear configuration stabilized by a non-covalent interaction network. The elucidation of these intricate molecular relationships holds promise for advancing our understanding of pathogenic mechanisms and facilitating the development of treatments for this severe neurodegenerative disorder.