4ZDP

The crystal structure of Y334C mutant of human SepSecS in complex with selenocysteine tRNA (tRNASec)

Summary for 4ZDP

• Entry DOI: 10.2210/pdb4zdp/pdb
• Related: 3HL2 4ZDL 4ZDO
• Descriptor: O-phosphoseryl-tRNA(Sec) selenium transferase, selenocysteine tRNA, (5-HYDROXY-4,6-DIMETHYLPYRIDIN-3-YL)METHYL DIHYDROGEN PHOSPHATE, ... (5 entities in total)
• Functional Keywords: selenocysteine, trna, mutation, pyridoxal phosphate, transferase-rna complex, transferase/rna
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 5
• Total formula weight: 252245.75

Authors

French, R.L.,Simonovic, M. (deposition date: 2015-04-17, release date: 2016-04-20, Last modification date: 2024-11-20)

Primary citation

Puppala, A.K.,French, R.L.,Matthies, D.,Baxa, U.,Subramaniam, S.,Simonovic, M.
Structural basis for early-onset neurological disorders caused by mutations in human selenocysteine synthase.
Sci Rep, 6:32563-32563, 2016

PubMed Abstract: 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.

PubMed: 27576344
DOI: 10.1038/srep32563

Experimental method

X-RAY DIFFRACTION (2.703 Å)