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New subunits of SPT: New insights into LCB diversity and human disease
Author(s) -
Dunn Teresa M,
Harmon Jeffrey M,
Han Gongshe,
Gable Kenneth,
Bacikova Dagmar,
Gupta Sita D,
Niranjanakumari Somashekarappa
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.197.4
Subject(s) - isozyme , gene isoform , protein subunit , transmembrane domain , biochemistry , amino acid , cytosol , mutant , transmembrane protein , phenotype , alanine , biology , peptide sequence , amino acid residue , enzyme , active site , yeast , hek 293 cells , saccharomyces cerevisiae , genetics , gene , receptor
Mammalian SPT was originally believed to be a heterodimer of LCB1/SPTLC1 and LCB2a/SPTLC2, but identification of a second LCB2 isoform (Lcb2b/SPTLC3) and the discovery of two small activating subunits, ssSPTa and ssSPTb, has made clear that there are several SPT isozymes. Expression of the human subunits in yeast revealed that isozymes containing ssSPTa have a preference for C16‐CoA while those with ssSPTb prefer C18‐CoA. Remarkably, this preference has been mapped to a single amino acid, which when changed to the corresponding residue of the other isoform flips acyl‐CoA preference. Based on deletion and topology studies, this residue lies in a short cytosolic tail N‐terminal to a single transmembrane domain (TMD) within a 35‐amino acid core sufficient for full activation. Many of the conserved residues of the ssSPTs reside within the predicted TMD suggesting that interactions between the ssSPTs and the heterodimer are within the membrane. Discovery of the ssSPTs has also provided insight into HSAN1, the most common hereditary sensory neuropathy, which results from mutations in the catalytic subunits of SPT. Originally believed to be catalytically inactive, when expressed with the ssSPTs, the mutant heterotrimers have significant activity and the mutations perturb the active site to allow utilization of alanine as a substrate resulting in the synthesis of deoxy‐LCBs that apparently underlie the HSAN1 phenotype.