期刊
NEUROMOLECULAR MEDICINE
卷 17, 期 1, 页码 47-57出版社
HUMANA PRESS INC
DOI: 10.1007/s12017-014-8339-1
关键词
Serine palmitoyltransferase; 1-Deoxysphingolipids; Sensory neuropathy; HSAN1; Sphingolipids
资金
- Medical Research Council MRC Centre Grant [G0601943]
- NINDS/ORD [1U54NS065712-01]
- Department of Health's National Institute for Health Research Biomedical Research Centers funding scheme
- Medical Research Council [G0802760, G0601943, G1001253, MR/K000608/1, G108/638, MR/J004758/1] Funding Source: researchfish
- MRC [G0802760, MR/J004758/1, G0601943, G1001253, G108/638, MR/K000608/1] Funding Source: UKRI
1-Deoxysphingolipids (1-deoxySL) are atypical sphingolipids that are formed by the enzyme serine palmitoyltransferase (SPT) due to a promiscuous use of l-alanine over its canonical substrate l-serine. Several mutations in SPT are associated with the hereditary sensory and autonomic neuropathy type I (HSAN1). The current hypothesis is that these mutations induce a permanent shift in the affinity from l-serine toward l-alanine which results in a pathologically increased 1-deoxySL formation in HSAN1 patients. Also, wild-type SPT forms 1-deoxySL under certain conditions, and elevated levels were found in individuals with the metabolic syndrome and diabetes. However, the molecular mechanisms which control the substrate shift of the wild-type enzyme are not understood. Here, we report a novel SPTLC2-S384F variant in two unrelated HSAN1 families. Affected patients showed elevated plasma 1-deoxySL levels and expression of the S384F mutant in HEK293 cells increased 1-deoxySL formation. Previously, S384 has been reported as one of the two (S384 and Y387) putative phosphorylation sites in SPTLC2. The phosphorylation of wild-type SPTLC2 was confirmed by isoelectric focusing. The impact of an S384 phosphorylation on SPT activity was tested by creating mutants mimicking either a constitutively phosphorylated (S384D, S384E) or non-phosphorylated (S384A, Y387F, Y387F+S384A) protein. The S384D but not the S384E variant was associated with increased 1-deoxySL formation. The other mutations had no influence on activity and substrate affinity. In summary, our data show that S384F is a novel mutation in HSAN1 and that the substrate specificity of wild-type SPT might by dynamically regulated by a phosphorylation at this position.
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