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Int. J. Mol. Sci. 2016, 17(1), 77; doi:10.3390/ijms17010077

Revealing the Effects of Missense Mutations Causing Snyder-Robinson Syndrome on the Stability and Dimerization of Spermine Synthase

1
Computational Biophysics and Bioinformatics, Clemson University, Clemson, SC 29634, USA
2
Greenwood Genetic Center, Greenwood, SC 29646, USA
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Academic Editor: William Chi-shing Cho
Received: 14 November 2015 / Revised: 28 December 2015 / Accepted: 4 January 2016 / Published: 8 January 2016
(This article belongs to the Collection Human Single Nucleotide Polymorphisms and Disease Diagnostics)
View Full-Text   |   Download PDF [1383 KB, uploaded 8 January 2016]   |  

Abstract

Missense mutations in spermine synthase (SpmSyn) protein have been shown to cause the Snyder-Robinson syndrome (SRS). Depending on the location within the structure of SpmSyn and type of amino acid substitution, different mechanisms resulting in SRS were proposed. Here we focus on naturally occurring amino acid substitutions causing SRS, which are situated away from the active center of SpmSyn and thus are not directly involved in the catalysis. Two of the mutations, M35R and P112L, are reported for the first time in this study. It is demonstrated, both experimentally and computationally, that for such mutations the major effect resulting in dysfunctional SpmSyn is the destabilization of the protein. In vitro experiments indicated either no presence or very little amount of the mutant SpmSyn in patient cells. In silico modeling predicted that all studied mutations in this work destabilize SpmSyn and some of them abolish homo-dimer formation. Since dimerization and structural stability are equally important for the wild type function of SpmSyn, it is proposed that the SRS caused by mutations occurring in the N-domain of SpmSyn is a result of dysfunctional mutant proteins being partially unfolded and degraded by the proteomic machinery of the cell or being unable to form a homo-dimer. View Full-Text
Keywords: missense mutation; energy calculations; Snyder-Robinson syndrome; spermine synthase; binding affinity charge missense mutation; energy calculations; Snyder-Robinson syndrome; spermine synthase; binding affinity charge
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Peng, Y.; Norris, J.; Schwartz, C.; Alexov, E. Revealing the Effects of Missense Mutations Causing Snyder-Robinson Syndrome on the Stability and Dimerization of Spermine Synthase. Int. J. Mol. Sci. 2016, 17, 77.

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