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Conformational Dynamics and Molecular Characterization of MORN motifs to shed light on homophilic interactions driving the formation of protein macromolecular superassemblies

Riccardo Tortarolo

Conformational Dynamics and Molecular Characterization of MORN motifs to shed light on homophilic interactions driving the formation of protein macromolecular superassemblies.

Rel. Marco Agostino Deriu, Marcello Miceli. Politecnico di Torino, Corso di laurea magistrale in Ingegneria Biomedica, 2021

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Abstract:

Membrane Occupation Recognition Nexus (MORN) motifs are protein domains poorly characterized despite the fact of being widely diffuse among different species in both eucaryotic and procaryotic organisms. These motifs are characterized by several repetitions of an highly conserved β-harpins modules. Experimental evidence is often conflicting showing a possible lipids binding activity as well as a protein-protein interaction capability. In mammalian MORN repetitions are found in Alsin, a multiple domain protein of 1657 amino acids transcripted from Amyotrophic Lateral Sclerosis type 2 (ALS2) gene, whose mutations are associated with Infantile-onset Ascending Hereditary Spastic Paralysis (IAHSP) disease. IAHSP is a rare neurodegenerative condition whose symptoms start to occur from the first years of life manifesting lower limbs spasticity and usually worsening also affecting the upper limbs and reaching tetraplegia. Literature evidence suggest that ALS2 MORN domains are involved in homophilic interactions to form an Alsin tetrameric form and binding activity of the guanosine triphosphatase Rab5. However, the relationship between Alsin protein biological functions and its three-dimensional structure is still unknown since, to our knowledge, no 3D models are available. In this work we assessed lack of such 3D model for ALS2 MORN and investigated its structural properties and potential dimeric state. We started by characterizing, through Molecular Dynamics (MD) methods, the geometry of three MORN dimeric assemblies from Trypanosoma brucei, Plasmodium falciparum and Toxoplasma gondii whose 3D structures are known from crystallography data of a recent study. Then we developed a first homology model of ALS2 MORN domain trough Computational Molecular Modelling methods and we validated it by comparing our best model with the best one generated from the ITasser suite. Based on the previous results, we finally built homology models of two possible dimeric conformations: a linear assembly and a V-shaped one. Their validation was based on comparison with the results of the previous three Results suggest that Alsin MORN domains are stable and seems to favour a V-shaped homophilic interaction rather than a more linear one giving a new insight into conformational characterization for the dimerization process of the Alsin.

Relators: Marco Agostino Deriu, Marcello Miceli
Academic year: 2020/21
Publication type: Electronic
Number of Pages: 72
Subjects:
Corso di laurea: Corso di laurea magistrale in Ingegneria Biomedica
Classe di laurea: New organization > Master science > LM-21 - BIOMEDICAL ENGINEERING
Aziende collaboratrici: Politecnico di Torino
URI: http://webthesis.biblio.polito.it/id/eprint/19672
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