The high mobility group (HMG) proteins are a superfamily of abundant and ubiquitous nuclear proteins that bind to DNA and nucleosomes and induce structural changes in the chromatin fiber.
An early report showed that non-histone chromosomal proteins NHCP extracted with 0.35 M NaCl from calf thymus chromatin can be fractionated into two main groups by trichloroacetic acid precipitation. These groups were named on the basis of their respective mobilities in 20% polyacrylamide gels at pH 2.4. The NHCP with low electrophoretic mobilities were called low mobility group (LMG) proteins and those with high electrophoretic mobilities were named high mobility group (HMG) proteins1.
The HMG protein family consists of six proteins and is subdivided into three subfamilies: the HMG-1/-2 subfamily, the HMG-I/Y subfamily and the HMG-14/-17 subfamily. The HMG-1 domain (often referred to as the HMG-1 box) is the functional motif of the largest HMG subfamily, the HMG-1/-2 proteins; the AT hook is the functional motif of the HMG-I/Y group, and the nucleosomal binding domain is the functional motif of the HMG-14/-17 subfamily.
The HMG-1 domain consists of approximately 80 amino acids and has a characteristic, twisted, L-shaped fold formed by three -helical segments2.
The AT hook motif is a positively charged stretch of 9 amino acids containing the invariant tripeptide GlyArgPro (GRP), usually flanked by arginine residues3.
The nucleosomal binding domain motif HMG-14 and HMG-17 protein is a positively charged stretch of approximately 30 amino acids with a bipartite structure: the amino-terminal region is extremely conserved and enriched in arginine residues, while the carboxyl-terminal region is highly enriched in lysine and proline residues4.
Mode of Action
The HMG-1 domain binds to and bends the minor groove of the DNA- The HMG-1 domain binds the DNA exclusively through the minor groove. A wedge of hydrophobic amino acids protruding from the concave surface of the protein partially intercalates between the DNA bases, expanding the minor groove, thereby significantly unwinding and bending the DNA. The amino acid sequence in the helical regions of the L-shaped HMG-1 domain provides specificity in DNA binding, while the type of intercalating amino acids and the angle of the L-shaped fold affect the degree to which the DNA is unwound and bent2.
The AT hook tethers proteins to and unbends the minor groove of the DNA The AT hook binds to the DNA through the minor groove with the optimal DNA binding site centered at the sequence AA(T/A)T. The AT hook has a narrow DNA recognition surface which is devoid of hydrophobic amino acids and does not significantly distort the B-form DNA structure3.
The nucleosomal binding domain anchors HMG-14 and HMG-17 proteins to nucleosomes The two proteins bind to nucleosomes cooperatively and form complexes containing either two molecules of HMG-14 or two molecules of HMG-17 but not complexes containing one molecule of each protein. The main function of these proteins is to change the architecture of the higher-order chromatin structure, mediated through the C-terminal region of the proteins. The nucleosomal binding domain anchors these HMG proteins to the nucleosome cores to facilitate HMG-14/-17-dependent changes in chromatin structure4.
High mobility group protein-1 (HMG-1) is a unique activator of p53 –A study showed that a HMG-1 factor from HeLa nuclear extracts activated p53 DNA binding. It was also demonstrated that recombinant His-tagged HMG-1 enhances p53 DNA binding in vitro and also that HMG-1 and p53 can interact directly in vitro. Further it has been shown that, HMG-1 also stimulates DNA binding by p53D30, a carboxy-terminally deleted form of the protein that is considered to be constitutively active, suggesting that HMG-1 stimulates p53 by a mechanism that is distinct from other known p53 activators5.
High Mobility Group Proteins 14 and 17 Can Prevent the Close Packing of Nucleosomes by Increasing the Strength of Protein Contacts in the Linker DNA - A study shows that digestion of HMG containing chromatin with micrococcal nuclease produces DNA fragments that were approximately 10 and 20 base pairs longer than nucleosome core-particle DNA. This suggests that HMG 14 or HMG 17 can protect, directly or indirectly, at least an additional 10 base pairs of linker DNA from micrococcal digestion. Also there is evidence that extensive micrococcal nuclease digestion of chromatin deficient in histones H2A/H2B led to the accumulation of DNA fragments about 110 base pairs in length, which is presumably the length of DNA associated with a nucleosomal particle deficient in one H2A/H2B dimer. Incorporation of either HMG 14 or HMG 17 into this chromatin results in the disappearance of this band and increase in the accumulation of fragments around 140-150 base pairs in length. In contrast to spacing of complete nucleosomes, it was found that the nucleosome binding domain of HMG 17 (but not the nucleosome binding of HMG 14) is the only domain required for spacing of H2A/H2B-deficient chromatin6.
1. Goodwin G (1998). The high mobility group protein, HMGI-C. Int. J. Biochem. Cell Biol., 30, 761-766.
2. Bustin M, and R Reeves (1996). High mobility group chromosomal proteins: architectural components that facilitate chromatin function. Prog. Nucleic Acid Res. Mol. Biol., 54, 35-100.
3. Aravind L and D Landsman (1998). AT-hook motifs identified in a wide variety of DNA-binding proteins. Nucleic Acids Res., 26, 4413-4421
4. Postnikov YV, L Trieschmann, Rickers, and Bustin (1995). Homodimers of chromosomal proteins HMG-14 and HMG-17 in nucleosome cores. J. Mol. Biol. 252, 423-432.
5. Lata Jayaraman, Narayani Chandra Moorthy, Kanneganti GK. Murthy, et al. (1998). High mobility group protein-1 (HMG-1) is a unique activator of p53. Genes Dev., 12, 462-472.
6. Bernard Degryse , Tiziana Bonaldi , Paola Scaffidi , Susanne Müller , Massimo Resnati , Francesca Sanvito , Gianluigi Arrigoni , and Marco E Bianchi (2001). High Mobility Group Proteins 14 and 17 Can Prevent the Close Packing of Nucleosomes by Increasing the Strength of Protein Contacts in the Linker DNA. The Journal of Cell Biology., 52(6), 1197-1206.
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