Citrin (the protein product of Slc25a13) is a member of the mitochondrial carrier family of proteins and catalyzes the calcium-dependent exchange of cytoplasmic glutamate with mitochondrial aspartate across the mitochondrial inner membrane [ 18– 20].
Thus, nrd2 1 was renamed nrpd2a-54 anrd2 22–2 was renamed nrpd2a-55 following the nrpd2a allele counting by Lopez et al. The G→A transition in nrpd2a-54 leads to an exchange of a glutamate for a lysine at position 1079 of the protein, while the G→A transition in nrpd2a-55 leads to a substitution of a glycine for an aspartate at position 174.
This explains why exchanges of the median glutamate to either alanine or glutamine lead to residual activities of below 1% (Fig. 1).
In addition, glutamate homoeostasis is also regulated by system xc−, a membrane-bound, Cl−-dependent, Na+-independent antiporter that mediates the cellular uptake of cystine in a 1 1 exchange for glutamate (Conrad and Sato, 2012).
This transporter imports one molecule of cystine from outside the cell in exchange for one molecule of glutamate from inside the cell.
System xc–, consisting of a catalytic light chain xCT (functional subunit of the cystine/glutamate transporter xc− system) [or SLC7A11 (solute carrier family 7 member 11)] and a regulatory heavy chain (4F2hc), transports cystine into cells in exchange for the release of glutamate at a 1 1 ratio.
Single and double exchange of D6 and D7 to alanine in peptide 1 gave analogues 3– 5, and exchange to glutamate gave 6– 8.
Of note, erastin inhibits system xC−, an heterodimeric antiporter of the plasma membrane that normally exchanges intracellular glutamate for extracellular cysteine, resulting in glutathione depletion and iron-dependent accumulation of reactive oxygen species.
Most BRAF mutations are missense mutations at amino acid position 600, resulting in an exchange of valine for glutamate (referred to as BRAFV600E).
The majority of analysed samples exhibited one specific B-Raf alteration that caused the exchange of valine to glutamate, a negatively charged amino acid, at position 599 (V599E) in the kinase domain of the protein.
