Cys2–His2 zinc fingers consist of a 30-amino acid residue sequence, which is folded around a zinc ion to form a stable structure (1). Zinc fingers are DNA-binding motifs and occur repeated in tandem. At least two adjacent zinc fingers appear to be necessary for binding (2). The zinc finger is an independent folding motif (3) consisting of a small β-sheet and an α-helix stabilized in a compact globular structure by the bound zinc (4-6). Base-specific contacts are made in the major groove of DNA and are mediated by amino acids in positions −1, 2, 3 and 6 of the α-helical “reading head” (4-6). The role of the linkers between finger domains is not as clear; linkers may make no contacts with DNA and do not affect the relative orientation of adjacent fingers (5), but in some cases they appear to participate in DNA-protein interactions (6). In the case of at least three zinc finger proteins, several amino acids N-terminal to the first finger are necessary for specific DNA binding. For the yeast transcription factor ADR1, containing two zinc finger motifs, it was demonstrated that residues outside zinc finger motif are important for DNA binding (7-9). Eleven residues N-terminal to the formal start of the first finger motif of yeast SWI5 protein are essential for stabilizing the folded form of finger 1 and for DNA binding (3). Furthermore, seven residues N-terminal to the first finger were shown to be required for sequence-specific DNA binding of Tramtrack protein (10).
To clarify the role of the N-terminal peptide preceding the zinc finger domain, we have studied the Tramtrack protein (Ttk)1 from Drosophila melanogaster. Ttk is involved in the regulation ofDrosophila embryonic development, and it binds to at least four DNA-binding sites (11, 12). Ttk is a sequence-specific DNA-binding protein, which contains two adjacent zinc fingers. The 66-residue DNA-binding domain (TTK DBD) is able to bind DNA specifically (10). Seven residues N-terminal to the first finger motif of TTK DBD are essential for DNA binding (10). The crystal structure of the domain complexed with DNA is known (5). The overall three-dimensional structure of the Ttk zinc fingers is the same as that of other zinc finger proteins. In this structure three residues N-terminal to the conventional finger motif fold to form a third strand to the β-sheet, although they lie too distant from the DNA to interact directly with DNA bases (5). The goal of our study was to investigate Ttk binding to DNA in solution and to compare the results with the crystallographic data. This was accomplished by cross-linking of TTK DBD with DNA, which was activated by partial depurination. Covalent adduct formation between activated DNA and the protein implied that the amino acid residue was in close proximity to the individual apurinic DNA site (13-16). We have identified the traced contacts of TTK DBD on the level of amino acids and DNA base pairs. It emerged that the TTK DBD N terminus cross-linked to the DNA base pairs corresponding to both specific and nonspecific binding. Thus, Ttk accessory peptide N-terminal to the first zinc finger is involved in the direct interaction with DNA like ADR1 (8, 9).
https://www.ncbi.nlm.nih.gov/pubmed/30718982
Best matches for Tramtrack domain:
Broad-complex, tramtrack, and bric-à-brac (BTB) proteins: Critical regulators of development.
Chaharbakhshi E et al. Genesis.
(2016)
Heat shock protein 90 maintains the stability and function of transcription factor Broad Z7 by interacting with its Broad-Complex-Tramtrack-Bric-a-brac domain.
Cai MJ et al. Insect Mol Biol.
(2014)
Evolutionary divergence in the broad complex, tramtrack and bric à brac/poxviruses and zinc finger domain from the candidate tumor suppressor gene hypermethylated in cancer.
Guerardel C et al. FEBS Lett.
(1999) Hypermethylated in cancer, a new candidate tumor suppressor gene located in 17p13.3, encodes a protein with five Krüppel-like C2H2 zinc finger motifs and a N-terminal protein/protein interaction domain called broad complex, tramtrack and bric à brac/poxviruses and zinc finger domain. Hypermethylated in cancer appears unique in the broad complex, tramtrack
and bric à brac/poxviruses and zinc finger family since it contains a
13 amino acid insertion located in a loop between the conserved
beta-strand beta5 and helix alpha5 which are involved in dimerization
and scaffolding of the broad complex, tramtrack and bric à brac/poxviruses and zinc finger domain.
Cloning and sequencing of a murine hypermethylated in cancer gene
suggests that this insertion has been acquired late in the evolution
since it is present in two mammalian hypermethylated in cancer genes but
absent in its zebrafish and avian counterparts. This is a unique
example of a high divergence of the same broad complex, tramtrack and bric à brac/poxviruses and zinc finger domain in different species.
- KELCHin kaltaisissa proteiineissa(KLHL) on tramtrack BTB-motiivissa.
Pharmacol Res. 2019 Aug 20;148:104404. doi: 10.1016/j.phrs.2019.104404. [Epub ahead of print]Kelch-like proteins: Physiological functions and relationships with diseases.Shi X1, Xiang S1, Cao J1, Zhu H1, Yang B1, He Q1, Ying M2.
Abstract
Kelch-like gene family members (KLHLs) encode proteins with a bric-a-brac, tramtrack, broad complex (BTB)/poxvirus and zinc finger (POZ) domain, a BACK domain,
and six Kelch motifs, which frequently interact with Cullin3 to form E3
ligase complexes that mediate the ubiquitination of substrate proteins.
In recent years, studies have revealed that mutations and abnormal
expression of KLHLs are closely related to the pathogenesis of various
human diseases. Increasing evidence has shown that Kelch-like protein
family members (KLHLs) exert important biological functions through the
ubiquitination of specific substrates. This review provides an overview
of the identified substrates of different KLHLs, summarizes the current
knowledge of KLHLs and discusses the biological functions of KLHLs in
different diseases.
Copyright © 2019 Elsevier Ltd. All rights reserved.KEYWORDS:
Cancer;
Chronic dieases; Dimethyl fumarate (PubChem CID: 637568); E3 ligase;
Hereditary diseases; KLHLs; ML334/LH601A (PubChem CID: 56840728);
Nutlin-3A (PubChem CID: 11433190); Substrate; Ubiquitination
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