Conformational Dynamics and Molecular Characterization of Alsin MORN
monomer and dimeric assemblies
Abstract
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.
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