LEU3 encodes a transcription factor that regulates the transcription of genes encoding enzymes involved in branched-chain amino acid synthesis (1). It is a member of the zinc cluster protein family, containing six conserved cysteines that bind two zinc ions in a binuclear cluster (2), Zn(II)2Cys6 genes reviewed in (7).

The Leu3 protein consists of the following five domains:

• zinc cluster DNA binding domain from amino acids 37-67, which is similar to the Gal4 DNA binding domain (8).
• linker region that specifies binding to the everted repeat (rather than a palindrome or direct repeat) target site (9, 3).
• alpha-helix/heptad repeat domain from amino acids 85-102 involved in dimerization (8).
• middle region that is involved in the regulation of Leu3p by alpha-IPM (see below) (10, 3, 8).
• acidic activation domain from amino acids 856-886 (8, 3).

The Leu3p target site is an everted repeat, not a palindrome or direct repeat (11); Leu3p binds this CCG-N4-CGG sequence as a homodimer (12). The four basepair spacing is necessary for recognition by Leu3p; altering the spacing to three or five abolishes binding (11). The activity of Leu3p is positively regulated by alpha-isopropylmalate (IPM), the product of the first step in leucine biosynthesis (5). The absence of IPM promotes intramolecular Leu3p interactions between the Leu3p activation domain and the middle region. This results in the masking of the Leu3p activation domain (3, 8). This regulation does not affect Leu3p nuclear localization or DNA binding, as Leu3p is constitutively bound to its target sites (13). The degree of activation by Leu3p is Leu3p concentration dependent, and it has been shown that LEU3 gene expression is regulated by general amino acid control, which is mediated by the Gcn4 transcription factor (2, 8).
Several genes whose expression is regulated by Leu3p have been identified, including LEU1(1), LEU2(1, 11), LEU4(1), ILV2(1), ILV5(1), GDH1(14), and BAP2(15).

Last updated: 2002-05-20