Structural basis for early-onset neurological disorders caused by mutations in human selenocysteine synthase

• Published in: Scientific reports Vol. 6; no. 1; p. 32563
• Main Authors: Puppala, Anupama K, French, Rachel L, Matthies, Doreen, Baxa, Ulrich, Subramaniam, Sriram, Simonović, Miljan
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 31.08.2016
• Subjects: Age; Age of Onset; Amino Acid Substitution; Amino Acyl-tRNA Synthetases - chemistry; Amino Acyl-tRNA Synthetases - genetics; Amino Acyl-tRNA Synthetases - metabolism; Ataxia; Ataxia - enzymology; Ataxia - genetics; Ataxia - pathology; Atrophy; Autosomal recessive inheritance; Binding Sites; Cerebellum; Cerebellum - enzymology; Cerebellum - pathology; Cerebral Cortex - enzymology; Cerebral Cortex - pathology; Children; Crystallography, X-Ray; Enzymes; Heredity; Humans; Irritable Mood; Models, Molecular; Muscle Spasticity - enzymology; Muscle Spasticity - genetics; Muscle Spasticity - pathology; Mutation; Neurological diseases; Neurological disorders; Population genetics; Protein Binding; Protein biosynthesis; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Folding; Protein Interaction Domains and Motifs; Protein Stability; Proteins; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; RNA, Transfer - chemistry; RNA, Transfer - metabolism; Seizures; Seizures - enzymology; Seizures - genetics; Seizures - pathology; Selenocysteine; Selenocysteine - chemistry; Selenocysteine - metabolism; Spasticity; Substrate Specificity
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep32563

Selenocysteine synthase (SepSecS) catalyzes the terminal reaction of selenocysteine, and is vital for human selenoproteome integrity. Autosomal recessive inheritance of mutations in SepSecS-Ala239Thr, Thr325Ser, Tyr334Cys and Tyr429*-induced severe, early-onset, neurological disorders in distinct human populations. Although harboring different mutant alleles, patients presented remarkably similar phenotypes typified by cerebellar and cerebral atrophy, seizures, irritability, ataxia, and extreme spasticity. However, it has remained unclear how these genetic alterations affected the structure of SepSecS and subsequently elicited the development of a neurological pathology. Herein, our biophysical and structural characterization demonstrates that, with the exception of Tyr429*, pathogenic mutations decrease protein stability and trigger protein misfolding. We propose that the reduced stability and increased propensity towards misfolding are the main causes for the loss of SepSecS activity in afflicted patients, and that these factors contribute to disease progression. We also suggest that misfolding of enzymes regulating protein synthesis should be considered in the diagnosis and study of childhood neurological disorders.