Biochemistry of the tale transcription factors PREP, MEIS, and PBX in vertebrates

Abstract

TALE (three amino acids loop extension) homeodomain transcription factors are required in various steps of embryo development, in many adult physiological functions, and are involved in important pathologies. This review focuses on the PREP, MEIS, and PBX sub-families of TALE factors and aims at giving information on their biochemical properties, i.e., structure, interactors, and interaction surfaces. Members of the three sets of protein form dimers in which the common partner is PBX but they can also directly interact with other proteins forming higher-order complexes, in particular HOX. Finally, recent advances in determining the genome-wide DNA-binding sites of PREP1, MEIS1, and PBX1, and their partial correspondence with the binding sites of some HOX proteins, are reviewed. These studies have generated a few general rules that can be applied to all members of the three gene families. PREP and MEIS recognize slightly different consensus sequences: PREP prefers to bind to promoters and to have PBX as a DNA-binding partner; MEIS prefers HOX as partner, and both PREP and MEIS drive PBX to their own binding sites. This outlines the clear individuality of the PREP and MEIS proteins, the former mostly devoted to basic cellular functions, the latter more to developmental functions.

Keywords: PREP, MEIS, and PBX; TALE proteins; vertebrates.

Figure 1

Phylogenesis and basic structure of the TALE proteins. A: Cladogram representing the phylogenetic relationship between the TALE-superfamily members of zebrafish, mouse, and human. The alignment of peptide sequences was performed using “ClustalW” software, the amino acid substitutions per site are indicated in every branch. Individual proteins are identified by the species (Hs, Homo sapiens; Mm, Mus musculus; Dr, Danio rerio). B: Basic features of the TALE proteins. The homeodomain (HD) is conserved throughout the whole group. The amino-terminal regions are family specific, since PBC-A and -B domains are found only in the PBX family while MEIS-A and -B in both Prep and Meis subfamilies. The location of the NES and NLS is also shown.

Figure 2

Conserved domains in human Meis and Prep proteins. A: Comparison of the main domains in human Meis1, Meis2, Meis3, Prep1, Prep2, and Drosophila hth proteins. On top the aminoacid sequence of Meis-A domain. The list on the right indicates the corresponding protein. In the middle, the Meis-B domain; at the bottom, the HD domain. In Meis-A domain, the binding sequences for Pbx1, P160, and 4EHP are highlighted in green. Accession numbers are: hMeis1: O00470; hMeis2: O14770; hMeis3: Q99687; Hth: NP_476578; hPrep1: NP_004562; hPrep2: CAD01142.

Figure 3

Sequence comparison of human Pbx proteins and Drosophila Exd. Alignment of full-length proteins was performed using ClustalW2 software. Stars indicate conserved amino acids. Magenta, the PBC-A domain; blue, the PBC-B domain; green, the HD domain Accession numbers are: Pbx1: AAG30941; Pbx2: P40425; Pbx3: P40426; Pbx4: CAC28212; Exd: AAC37182.1

Figure 4

The a and b isoforms of human and mouse Pbx1. The “a” forms are 430, the “b” forms 358 (H. sapiens) and 357 (M. musculus) residues long.