title: Revealing the Effects of Missense Mutations Causing Snyder-Robinson Syndrome on the Stability and Dimerization of Spermine Synthase.
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.
authors.affiliation: Computational Biophysics and Bioinformatics, Clemson University, Clemson, SC 29634, USA. yunhuip@g.clemson.edu.
authors.forename: Yunhui
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Greenwood Genetic Center, Greenwood, SC 29646, USA. jwnorris@ggc.org.
authors.forename: Joy
authors.initials: J
authors.lastname: Norris
authors.affiliation: Greenwood Genetic Center, Greenwood, SC 29646, USA. ceschwartz@ggc.org.
authors.forename: Charles
authors.initials: C
authors.lastname: Schwartz
authors.affiliation: Computational Biophysics and Bioinformatics, Clemson University, Clemson, SC 29634, USA. ealexov@clemson.edu.
authors.forename: Emil
authors.initials: E
authors.lastname: Alexov
mesh_terms: D000595:Amino Acid Sequence; D003198:Computer Simulation; D004795:Enzyme Stability; D006801:Humans; D038901:X-Linked Intellectual Disability / Q000201:enzymology* / Q000235:genetics*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D017510:Protein Folding; D055503:Protein Multimerization; D016415:Sequence Alignment; D013097:Spermine Synthase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D013097:Spermine Synthase
keywords: Snyder-Robinson syndrome; binding affinity charge; energy calculations; missense mutation; spermine synthase