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12th International Conference on STRUCTURAL AND MOLECULAR BIOLOGY

Osaka, Japan

Wei Li

Wei Li

Shantou University Medical College, China

Title: Title: How do SMA-linked mutations of SMN1 lead to structural/functional deficiency of the SMA protein?


Biography: Wei Li


Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease with dysfunctional α-motor neurons in the anterior horn of the spinal cord. SMA is caused by loss (~95% of SMA cases) or mutation (~5% of SMA cases) of the survival motor neuron 1 gene SMN1. As the product of SMN1, the SMN protein is a key component of the SMN complex, and also involved in the biosynthesis of the small nuclear ribonucleoproteins (snRNPs), which play critical roles in pre-mRNA splicing during the pathogenesis of SMA. To investigate how SMA-linked mutations of SMN1 lead to structural/functional deficiency of SMN, a set of computational analysis of SMN-related structures were conducted and are presented. Of extraordinary interest, the computational structural analysis highlights three SMN residues (Asp44, Glu134 and Gln136) with SMA-linked missense mutations, which cause local disruptions of electrostatic interactions for Asp44, Glu134 and Gln136, and result in three functionally deficient SMA-linked SMN mutants, Asp44Val, Glu134Lys and Gln136Glu. From the computational structural analysis, it appears also possible that SMN’s Lys45 and Asp36 act as two electrostatic clips at the SMN-Gemin2 complex structure interface, structurally stabilizing the SMN-Gemin2 complex. Moreover, the structural analysis of a group of four further SMA-linked mutations (Trp92Ser, Trp102X, Ala111Gly and Ile116Phe) highlight the potential significance of the deeply buried hydrophobic side chains of Trp92, Trp102, Ala111 and Ile116 in the SMN Tudor domain, the essential part of SMN for its ability to bind the Sm proteins of snRNPs