Erin Monaghan

Publications (2)6.67 Total impact

• Article: Mutations in the Lcb2p subunit of serine palmitoyltransferase eliminate the requirement for the TSC3 gene in Saccharomyces cerevisiae.

  Erin Monaghan, Ken Gable, Teresa Dunn
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  ABSTRACT: Serine palmitoyltransferase catalyses the committed step in sphingolipid synthesis, the condensation of serine with palmitoyl-CoA to form 3-ketosphinganine. Two proteins, Lcb1p and Lcb2p, are essential for enzyme activity and a third protein, the 80-amino acid Tsc3p, stimulates the activity of serine palmitoyltransferase several-fold. Tsc3p physically associates with a complex of Lcb1p-Lcb2p and stimulates enzyme activity posttranslationally, but its precise function is not known. Tsc3p is essential for cell viability only at elevated temperatures, although serine palmitoyltransferase activity is reduced in the tsc3 delta mutant, even at permissive growth temperatures. Tsc3p is apparently not required for any essential process besides stimulation of serine palmitoyltransferase at 37 degrees C, since providing sphingoid bases to the growth medium reverses the temperature-sensitive growth phenotype of the tsc3 delta mutant. To gain further insight into the function of Tsc3p, suppressor mutants that eliminate the Tsc3p requirement for growth at 37 degrees C were isolated and characterized. These studies show that dominant mutations in the Lcb2p subunit of serine palmitoyltransferase suppress the temperature-sensitive growth phenotype of the tsc3 delta null mutant by increasing the Tsc3p-independent serine palmitoyltransferase activity.
  Yeast 07/2002; 19(8):659-70. · 1.89 Impact Factor
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  Available from: digitalcommons.unl.edu

  Article: Mutations in the yeast LCB1 and LCB2 genes, including those corresponding to the hereditary sensory neuropathy type I mutations, dominantly inactivate serine palmitoyltransferase.

  Ken Gable, Gongshe Han, Erin Monaghan, Dagmar Bacikova, Mukil Natarajan, Robert Williams, Teresa M Dunn
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  ABSTRACT: It was recently demonstrated that mutations in the human SPTLC1 gene, encoding the Lcb1p subunit of serine palmitoyltransferase (SPT), cause hereditary sensory neuropathy type I . As a member of the subfamily of pyridoxal 5'-phosphate enzymes known as the alpha-oxoamine synthases, serine palmitoyltransferase catalyzes the committed step of sphingolipid synthesis. The residues that are mutated to cause hereditary sensory neuropathy type I reside in a highly conserved region of Lcb1p that is predicted to be a catalytic domain of Lcb1p on the basis of alignments with other members of the alpha-oxoamine synthase family. We found that the corresponding mutations in the LCB1 gene of Saccharomyces cerevisiae reduce serine palmitoyltransferase activity. These mutations are dominant and decrease serine palmitoyltransferase activity by 50% when the wild-type and mutant LCB1 alleles are coexpressed. We also show that serine palmitoyltransferase is an Lcb1p small middle dotLcb2p heterodimer and that the mutated Lcb1p proteins retain their ability to interact with Lcb2p. Modeling studies suggest that serine palmitoyltransferase is likely to have a single active site that lies at the Lcb1p small middle dotLcb2p interface and that the mutations in Lcb1p reside near the lysine in Lcb2p that is expected to form the Schiff's base with the pyridoxal 5'-phosphate cofactor. Furthermore, mutations in this lysine and in a histidine residue that is also predicted to be important for pyridoxal 5'-phosphate binding to Lcb2p also dominantly inactivate SPT similar to the hereditary sensory neuropathy type 1-like mutations in Lcb1p.
  Journal of Biological Chemistry 04/2002; 277(12):10194-200. · 4.77 Impact Factor