Summary information and primary citation
- PDB-id
-
4zdp;
DSSR-derived features in text and
JSON formats
- Class
- transferase-RNA
- Method
- X-ray (2.703 Å)
- Summary
- The crystal structure of y334c mutant of human sepsecs
in complex with selenocysteine trna (trnasec)
- Reference
-
Puppala AK, French RL, Matthies D, Baxa U, Subramaniam S,
Simonovic M (2016): "Structural
basis for early-onset neurological disorders caused by
mutations in human selenocysteine synthase." Sci
Rep, 6, 32563. doi: 10.1038/srep32563.
- 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.
