Spinal muscular atrophy (SMA) is a motor neuron disease that leads to muscle atrophy due to motor neurons degeneration. SMA is a major genetic cause of early childhood mortality and results from mutations in the Survival of Motor Neuron (SMN) gene1. The SMN protein plays a crucial role in the assembly of spliceosomal small nuclear ribonucleoprotein complexes via binding to the spliceosomal Sm core proteins, in particular to their arginine-glycine (RG) rich C-terminal tails. SMN contains a central Tudor domain, directly involved in the SMN–Sm protein interaction by the recognition of symmetrically dimethylated arginine (DMR) residues in the RG repeats. In particular, an aromatic cage on Tudor domain seems to mediate this binding (1–3). Six of the pathogenic mutations causing SMA occur in the SMN Tudor domain. The only one that prevents the binding to the Sm proteins without a perturbation of the domain fold is E134K, that is the cause of the more severe type I SMA (3). To gain more understanding about the mechanism by which SMN interacts with the Sm proteins, and which are the structural effects on binding of its deleterious mutation E134K, we investigated the behavior of the native and mutated structure of the SMN Tudor domain in the presence of the C-terminal tail of SmD1, by means of molecular dynamics simulations. The interaction of the SmD1 tail with the Tudor domain is electrostatic driven by the acidic residues near the entrance of the aromatic cage. A central DMR of the tail enters into the cage rapidly and stably, forming a network of cationic-pi interactions, both in stacking and T-shaped. The complex is stabilized also by the salt-bridges formed by the other DMRs and arginine residues wrapped around the acidic surface of the domain. The E134K mutation destabilizes the cage, not only with the disruption of the strong 134-136-127 H-bonds network, but also with the formation of new electrostatic and cationic-pi interactions. The cage collapses and expands, preventing a stable binding of the DMR. This is impeded also by the detachment of the C-terminal region of the tail from the Tudor domain, caused by the E134K charge inversion. The results are in agreement with what experimentally observed (1–3) and clarify the key role of E134 in the interaction of the SmD1 tail to the Tudor domain. The loss of a strong Tudor-SmD1 interaction, if by one side causes the loss of a functional splicing machinery, by the other side causes the exposition of the detached Sm tails, that could stimulate the recognition by anti-Sm autoantibodies, as is reported for other diseases as lupus erithematosus (4), giving rise to the innovative hypothesis of SMA as an autoimmune disease. 1. P. Selenko et al., Nat. Struct. Biol. 8, 27–31 (2001). 2. R. Sprangers et al., J. Mol. Biol. 327, 507–520 (2003). 3. K. Tripsianes et al., Nat. Struct. Mol. Biol. 18, 1414–20 (2011). 4. H. Brahms et al., J. Biol. Chem. 275, 17122–17129 (2000).

Inside the mechanism of SMN-SmD1 protein complex formation: effects of the Spinal Muscular Atrophy - causing E134K mutation. A molecular dynamics simulation study / E. Polverini; V. Gherardi. - (2014). ((Intervento presentato al convegno 13th European Conference on Computational Biology - ECCB14 tenutosi a Strasbourg nel 7-10 settembre 2014.

Inside the mechanism of SMN-SmD1 protein complex formation: effects of the Spinal Muscular Atrophy - causing E134K mutation. A molecular dynamics simulation study.

POLVERINI, Eugenia;
2014

Abstract

Spinal muscular atrophy (SMA) is a motor neuron disease that leads to muscle atrophy due to motor neurons degeneration. SMA is a major genetic cause of early childhood mortality and results from mutations in the Survival of Motor Neuron (SMN) gene1. The SMN protein plays a crucial role in the assembly of spliceosomal small nuclear ribonucleoprotein complexes via binding to the spliceosomal Sm core proteins, in particular to their arginine-glycine (RG) rich C-terminal tails. SMN contains a central Tudor domain, directly involved in the SMN–Sm protein interaction by the recognition of symmetrically dimethylated arginine (DMR) residues in the RG repeats. In particular, an aromatic cage on Tudor domain seems to mediate this binding (1–3). Six of the pathogenic mutations causing SMA occur in the SMN Tudor domain. The only one that prevents the binding to the Sm proteins without a perturbation of the domain fold is E134K, that is the cause of the more severe type I SMA (3). To gain more understanding about the mechanism by which SMN interacts with the Sm proteins, and which are the structural effects on binding of its deleterious mutation E134K, we investigated the behavior of the native and mutated structure of the SMN Tudor domain in the presence of the C-terminal tail of SmD1, by means of molecular dynamics simulations. The interaction of the SmD1 tail with the Tudor domain is electrostatic driven by the acidic residues near the entrance of the aromatic cage. A central DMR of the tail enters into the cage rapidly and stably, forming a network of cationic-pi interactions, both in stacking and T-shaped. The complex is stabilized also by the salt-bridges formed by the other DMRs and arginine residues wrapped around the acidic surface of the domain. The E134K mutation destabilizes the cage, not only with the disruption of the strong 134-136-127 H-bonds network, but also with the formation of new electrostatic and cationic-pi interactions. The cage collapses and expands, preventing a stable binding of the DMR. This is impeded also by the detachment of the C-terminal region of the tail from the Tudor domain, caused by the E134K charge inversion. The results are in agreement with what experimentally observed (1–3) and clarify the key role of E134 in the interaction of the SmD1 tail to the Tudor domain. The loss of a strong Tudor-SmD1 interaction, if by one side causes the loss of a functional splicing machinery, by the other side causes the exposition of the detached Sm tails, that could stimulate the recognition by anti-Sm autoantibodies, as is reported for other diseases as lupus erithematosus (4), giving rise to the innovative hypothesis of SMA as an autoimmune disease. 1. P. Selenko et al., Nat. Struct. Biol. 8, 27–31 (2001). 2. R. Sprangers et al., J. Mol. Biol. 327, 507–520 (2003). 3. K. Tripsianes et al., Nat. Struct. Mol. Biol. 18, 1414–20 (2011). 4. H. Brahms et al., J. Biol. Chem. 275, 17122–17129 (2000).
Inside the mechanism of SMN-SmD1 protein complex formation: effects of the Spinal Muscular Atrophy - causing E134K mutation. A molecular dynamics simulation study / E. Polverini; V. Gherardi. - (2014). ((Intervento presentato al convegno 13th European Conference on Computational Biology - ECCB14 tenutosi a Strasbourg nel 7-10 settembre 2014.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2762334
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