HMG Domain Superfamily of DNA‐bending Proteins: HMG, UBF, TCF, LEF, SOX, SRY and Related Proteins


SRY, the Y‐chromosome‐encoded male sex‐determining factor, is the signature member of a larger family of related transcription factors, the SOX proteins. SOX proteins are related by a DNA (deoxyribonucleic acid)‐binding domain known as the HMG (high mobility group) domain, which in turn unites a larger superfamily of proteins. SRY and SOX proteins are thought to regulate gene transcription through binding to specific DNA sequence motifs and causing the DNA to bend – a property of so‐called architectural transcription factors. Similarly, a related family of proteins, including TCF‐1 (T‐cell factor 1), LEF‐1 (lymphoid enhancer factor 1) and their relatives, regulates transcription by virtue of sequence‐specific DNA binding. A third family, the true or canonical HMG proteins, differs by containing multiple HMG domains, not binding to specific target DNA sequences, and having poorly defined roles. Here, we examine the diversity, origins, molecular functions and biological roles of the HMG domain superfamily.

Key Concepts:

  • The 80 amino acid HMG domain characterizes a superfamily of proteins found in plants and animals.

  • HMG domain proteins associate with DNA and usually bend it, thereby influencing transcription of genes.

  • The most ancient family of these proteins, represented by the canonical HMG proteins HMG‐1 and HMG‐2, have multiple HMG domains, and do not bind to any specific DNA sequences.

  • Genes encoding canonical HMG proteins may have evolved into two further families of genes encoding proteins that have single HMG domains and bind to specific DNA sequence motifs.

  • These families include SRY (the mammalian Y‐linked sex‐determining factor) and the SOX, TCF‐1 and LEF‐1 transcription factors.

  • Unlike canonical HMG proteins, these other HMG domain proteins have specific, important and well‐defined biological roles, particularly in embryonic development.

Keywords: HMG domain; DNA binding; DNA bending; transcription factors; SOX factors

Figure 1.

Phylogeny and nomenclature of the HMG domain superfamily and high mobility group proteins. (a) The HMG domain superfamily is structurally and evolutionarily related by the HMG domain. (b) On the other hand, the high mobility group proteins, defined by fast migration during electrophoresis, contain several types of protein, only one of which (the HMG‐1, HMG‐2 class) contains the 80 amino acid motif known as the HMG domain.

Figure 2.

Role of architectural transcription factors. (a) The region upstream of a hypothetical gene, with the start of the transcribed region shown as a solid bar. A, B and C represent sites for binding of regulatory proteins. In this example, B represents a binding site for an architectural transcription factor. (b) Binding of factor B (shaded oval), resulting in bending of the chromatin. As a result, binding sites for A and C are brought into proximity. (c) Binding of factors A and C then allows a complex of transcription factors to be built up (ovals and circles), such that transcription of the hypothetical gene is initiated (arrow).



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Koopman, Peter(Mar 2010) HMG Domain Superfamily of DNA‐bending Proteins: HMG, UBF, TCF, LEF, SOX, SRY and Related Proteins. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0002325.pub2]