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Review
. 2024 Aug 14;25(16):8863.
doi: 10.3390/ijms25168863.

Binding to the Other Side: The AT-Hook DNA-Binding Domain Allows Nuclear Factors to Exploit the DNA Minor Groove

Sabrina Battista  1 , Monica Fedele  1 , Luca Secco  2 , Alberto Maria Davide Ingo  2 , Riccardo Sgarra  2 , Guidalberto Manfioletti  2
Affiliations
Review

Binding to the Other Side: The AT-Hook DNA-Binding Domain Allows Nuclear Factors to Exploit the DNA Minor Groove

Sabrina Battista et al. Int J Mol Sci. .

Abstract

The "AT-hook" is a peculiar DNA-binding domain that interacts with DNA in the minor groove in correspondence to AT-rich sequences. This domain has been first described in the HMGA protein family of architectural factors and later in various transcription factors and chromatin proteins, often in association with major groove DNA-binding domains. In this review, using a literature search, we identified about one hundred AT-hook-containing proteins, mainly chromatin proteins and transcription factors. After considering the prototypes of AT-hook-containing proteins, the HMGA family, we review those that have been studied in more detail and that have been involved in various pathologies with a particular focus on cancer. This review shows that the AT-hook is a domain that gives proteins not only the ability to interact with DNA but also with RNA and proteins. This domain can have enzymatic activity and can influence the activity of the major groove DNA-binding domain and chromatin docking modules when present, and its activity can be modulated by post-translational modifications. Future research on the function of AT-hook-containing proteins will allow us to better decipher their function and contribution to the different pathologies and to eventually uncover their mutual influences.

Keywords: AKNA; AT-hook; BRG1; EBNA1; HMGA; LEDGF/p75; MLL1; MeCP2; PATZ1; ZFAT.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
An AT-hook sequence comparison. (A) Proteins whose AT-hook sequences are reported in the UniProt Knowledgebase have been included in the table. The sequences of their AT-hook are shown on the right side, and they are aligned, taking as a reference the GRP core (evidenced in black). Arginine (R), Lysine (K), and Proline (P) are evidenced with different colours. Four AT-hook sequences are missing the GRP core. (B) A graph depicting the relative abundance of amino acid in the AT-hooks is shown.
Figure 2
Figure 2
The AT-hook of HMGA1 binding to the minor groove of the DNA sequence. The AT-hook structure with DNA (space filling atoms) evidences the PRGRP core interacting with the inner part of the minor grove of the 5′-CGAATTAATTCG-3′ duplex DNA sequence while flanking basic residues contact the phosphate backbone (picture taken from Fonfría-Subirós et al. [11]).
Figure 3
Figure 3
The domain organisation of the AT-hook-containing proteins. A scheme of all the AT-hook-containing proteins described in the text is shown. The domain organisation of HMGA1a, HMGA1b, HMGA2, PATZ1, ZFAT, LEDGF/p75, MLL1, MeCP2, AKNA, BRG1, BRM, EBNA1, and spORC4 is shown. For each protein, the amino acid number is indicated. Proteins and domains are not in scale. POZ/BTB: POxvirus and Zinc finger/Broad-complex, Tramtrack and Bric a brac; NLS: nuclear localisation signal; CR: charged region; IBD: integrase-binding domain; PWWP: proline (P), tryptophan (W), tryptophan (W), proline (P) domain; MBM: menin-binding motif; LBD: LEDGF-binding domain; CxxC: CxxC domain; PHD: plant homology domain; BRD: bromodomain; FYRN: F/Y-rich N terminus domain; TAD: transactivation domain; FYRC: F/Y-rich C terminus domain; Win: WDR5 interaction motif; SET: Drosophila proteins Su(var)3-9, Enhancer-of-zeste and Trithorax domain; MBD: methyl-CpG-binding domain; TRD: transcriptional repression domain; PEST: proline [P]-, glutamic acid [E]-, serine [S]-, and threonine [T]-rich domain; QLQ: glutamin (Q), leucin (L), glutamin (Q) motif; HSA: helicase/SANT-associated domain; SnAC: Snf2-ATP coupling domain; GR: glycine (G)- and arginine (R)-rich domain; DBD: DNA-binding domain; UR: unique region; GA: glycine (G) and alanine (A) repeat region.
Figure 4
Figure 4
Competition between AT-hook-containing proteins. The AT-hook domain is involved in DNA, RNA, and protein binding. When an AT-hook-containing protein is over expressed, it is conceivable that it could compete with other AT-hook-containing factors. The competition could lead to the occupation of other lower-affinity binding sites, displacing them from targets and potentially changing the type of targets (i.e., DNA -> RNA or PROTEIN; RNA -> DNA or PROTEIN; PROTEIN -> DNA or RNA).
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