PROSITE documentation PDOC51062

Runt domain profile

The Runt domain is a ~128 amino acid region that is characteristic of the RUNX family of heterodimeric eukaryotic transcription factors. The family includes genes from drosophila, chicken and mammals that are involved in a wide range of developmental processes, from sex determination and neurogenesis in drosophila to hematopoiesis and osteoblast differentiation in mouse and human. The Runt domain confers DNA binding ability to the consensus core PyGPyGGT and mediates the interaction of mammalian RUNX proteins with the β-subunit, designated core-binding factor β (CBFβ), which increases the DNA binding affinity of the heterodimer [1,2].

The Runt domain adopts the fold of an immunoglobulin (Ig)-like β sandwich (see <PDB:1EAQ; B>). However, an N-terminal α helix, which precedes the Ig domain is also part of the evolutionary conserved Runt domain. The helix packs through hydrophobic interactions against the bulk of the domain that is formed by 12 β strands (10 antiparallel and two parallel strands). Two chloride ions bind to the native Runt domain of which one is situated at the DNA-binding surface. The transition from the uncomplexed Runt domain to the CBFβ and/or DNA-bound form is accompanied by considerable structural rearrangements. Once a Runt-CBFβ or a Runt-DNA complex has formed, almost identical changes accompany the transition from the binary Runt-CBFβ complex to the ternary complex including DNA and the transition from the binary Runt-DNA complex to the ternary complex with CBFβ, even though CBFβ and DNA bind to different surfaces on Runt. This suggests that the function of CBFβ is to convert the Runt domain into a DNA-binding competent conformation before actually binding to DNA and to stabilize this conformation [2].

Some proteins known to contain a Runt domain are listed below:

• Mammalian RUNX1 or acute myeloid leukemia protein 1 (AML1). It is together with CBFβ essential for hematopoiesis.
• Mammalian RUNX2 (AML3/PEBP2αA/CBFα1). It is essential for osteoblast differentiation and bone formation.
• Mammalian RUNX3. It is essential for antiproliferation and apoptosis of the gastric epithelium.
• Chicken runt B protein.
• Drosophila segmentation protein Runt. It plays a pivotal role in regulating the expression of other pair-rule genes such as eve, ftz, and h.
• Drosophila lozenge protein.

The profile we developed covers the entire Runt domain.