Dysregulation of a lipid transfer protein linked to brain disorders
Advanced studies of human genetics are a big wave in the medical sciences. Collaborative teams of clinical geneticists and bioinformaticians are surfing this wave, rapidly discovering genomic variations associated with specific human disorders. This trend is providing scientific bases for personalized medicines but also new, important questions linked to the basic biochemistry field.
Ceramide transport protein, or CERT, moves the waxy lipids known as ceramides in cells for the synthesis of sphingomyelin, a membrane lipid that is ubiquitous in mammalian cells. In 2007, researchers found that CERT is functionally repressed by multiple phosphorylations of a serine-repeat motif, or SRM, in CERT. At the time, scientists regarded this finding as pure biochemistry of a protein.
However, a decade later, large-scale human genetic studies on intellectual disabilities and mental development disorders, or ID/MD, showed that missense mutations in or near the CERT SRM-encoding regions are associated with a type of autosomal dominant hereditary ID/MD. The dominant inheritance was in line with a prediction from the previous biochemical study that loss of hyperphosphorylation of the SRM renders CERT abnormally active.
Our recent collaborative study confirmed this prediction by demonstrating that substitution of a serine residue in the SRM with other residues similar to variants found in ID/MD patients results in dysregulation of CERT in cultured cells. Nonetheless, several ID/MD-associated missense mutations that occurred in the CERT gene CERT1 also are mapped outside the SRM. This riddle was answered by another recent study showing that a non-SRM variant also compromises the SRM hyperphosphorylation, thereby abnormally activating CERT.
Moreover, cell biological analysis showed that abnormally activated CERT mutants exhibit an aberrant punctate distribution in cells, suggesting that the subcellular distribution pattern is applicable as a diagnostic tool to assess whether a CERT1 variant is an abnormally activated type that may cause ID/MD, although the precise identity of the puncta structure remains undetermined.
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They found that one mechanism of CK1 activity, and thus one mechanism of regulation, is the self-phosphorylation of a conserved amino acid residue in its catalytic domain.
“The phase preference of molecules used to be difficult and time-consuming to establish. This new method, detected by chance, provides results in at most 15 minutes on live cells,” Thorsten Wohland said.
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