4ZDL

The crystal structure of the T325S mutant of the human holo SepSecS

4ZDL の概要

• エントリーDOI: 10.2210/pdb4zdl/pdb
• 関連するPDBエントリー: 4ZDO 4ZDP
• 分子名称: O-phosphoseryl-tRNA(Sec) selenium transferase, (5-HYDROXY-4,6-DIMETHYLPYRIDIN-3-YL)METHYL DIHYDROGEN PHOSPHATE, CITRATE ANION, ... (4 entities in total)
• 機能のキーワード: selenocysteine, pyridoxal phosphate, mutation, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 112229.79

構造登録者

French, R.L.,Simonovic, M. (登録日: 2015-04-17, 公開日: 2016-04-20, 最終更新日: 2024-11-20)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.26 Å)