Human phosphoserine aminotransferase in complex with PLP

About this structure

L-phosphoserine aminotransferase (SERC) is a member of the Class V pyridoxal phosphate dependent aminotransferase family. It catalyses the second of three steps in L-serine production from 3-phosphoglycerate, the conversion of 3-phosphohydroxypyruvate to 3-phosphoserine, with the consumption of an L-glutamate. Besides its role in protein synthesis, L-serine can play a part in the biosynthesis of small amino acids, serine phospholipids, sphingomyelins and cerebrosides. It is also required for the synthesis of nucleotide precursors, such as purines and thymidine, which is directly linked to cellular replication [1].

SERC activity is found in a number of organs but is increased in tissues with a high rate of cell turnover. SERC is expressed at high levels in the brain, liver, kidney and pancreas, and at low levels in the thymus prostate, testis and colon [2]. Two isoforms of SERC, α and β, exist in human cells. The β isoform, which contains a 46-amino-acid insert between Val290 and Ser337, is the physiologically relevant one [1]. SERC deficiency is characterized biochemically by low concentrations of serine and glycine in plasma and cerebrospinal fluid (CSF), and clinically by intractable seizures, acquired microcephaly, hypertonia, and psychomotor retardation. Prognosis is poor once the individual becomes symptomatic, but treatment with serine and glycine supplementation from birth can lead to normal development [3]. SERC is overexpressed in colon adenocarcinoma [2] and increases with tumour stage in colon cancer [4]. SERC also stimulates the proliferation of colorectal cancer cells and modulates their chemotherapy sensitivity both in vitro and in vivo [5].

Here we present the crystal structure of SERC (residues Leu17 to Leu370) in complex with pyridoxal phosphate (PLP) at a resolution of 2.5Å. Similar to the structure of other members of this family of aminotransferases the protein consists of a homodimer with both monomers contributing to the PLP-containing active site at their interface. The individual monomers can be divided into two domains: The larger domain (residues Leu17 to Gly263) consists of six alpha helices and a seven stranded mostly parallel β-sheet, and binds PLP covalently through Lys200. The smaller domain consists of a two-stranded antiparallel β-sheet and three alpha helices. PLP is modelled into two of the monomers in the asymmetric unit while the third one lacks density for modelling of the cofactor. The presence of PLP does not appear to cause any significant structural changes. An active site loop (residues Met1 – Lys16) was not included in this protein construct; however similar residues from the affinity purification tag were found to rest in an orientation reminiscent of those of the active site loop of the MR model (E. coli serC PDB entry 1BJO).

References

1. Baek, J.Y., et al. (2003) Characterization of human phosphoserine aminotransferase involved in the phosphorylated pathway of L-serine biosynthesis. Biochem J 373: 191-200.
2. Ojala, P., et al. (2002) mRNA differential display of gene expression in colonic carcinoma. Electrophoresis 23: 1667-1676.
3. Hart, C.E., et al. (2007) Phosphoserine aminotransferase deficiency: a novel disorder of the serine biosynthesis pathway. Am J Hum Genet 80: 931-937.
4. Friederichs, J., et al. (2005) Gene expression profiles of different clinical stages of colorectal carcinoma: toward a molecular genetic understanding of tumor progression. Int J Colorectal Dis 20: 391-402.
5. Vie, N., et al. (2008) Overexpression of phosphoserine aminotransferase PSAT1 stimulates cell growth and increases chemoresistance of colon cancer cells. Mol Cancer 7: 14.