4ZDL
The crystal structure of the T325S mutant of the human holo SepSecS
Summary for 4ZDL
| Entry DOI | 10.2210/pdb4zdl/pdb |
| Related | 4ZDO 4ZDP |
| Descriptor | O-phosphoseryl-tRNA(Sec) selenium transferase, (5-HYDROXY-4,6-DIMETHYLPYRIDIN-3-YL)METHYL DIHYDROGEN PHOSPHATE, CITRATE ANION, ... (4 entities in total) |
| Functional Keywords | selenocysteine, pyridoxal phosphate, mutation, transferase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 112229.79 |
| 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 Cited by 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: 27576344DOI: 10.1038/srep32563 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.26 Å) |
Structure validation
Download full validation report
