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Review
. 2009 Jun;10(3):244-69.
doi: 10.2174/138920309788452164.

The importance of being flexible: the case of basic region leucine zipper transcriptional regulators

Maria Miller  1
Affiliations
Review

The importance of being flexible: the case of basic region leucine zipper transcriptional regulators

Maria Miller. Curr Protein Pept Sci. 2009 Jun.

Abstract

Large volumes of protein sequence and structure data acquired by proteomic studies led to the development of computational bioinformatic techniques that made possible the functional annotation and structural characterization of proteins based on their primary structure. It has become evident from genome-wide analyses that many proteins in eukaryotic cells are either completely disordered or contain long unstructured regions that are crucial for their biological functions. The content of disorder increases with evolution indicating a possibly important role of disorder in the regulation of cellular systems. Transcription factors are no exception and several proteins of this class have recently been characterized as premolten/molten globules. Yet, mammalian cells rely on these proteins to control expression of their 30,000 or so genes. Basic region:leucine zipper (bZIP) DNA-binding proteins constitute a major class of eukaryotic transcriptional regulators. This review discusses how conformational flexibility "built" into the amino acid sequence allows bZIP proteins to interact with a large number of diverse molecular partners and to accomplish their manifold cellular tasks in a strictly regulated and coordinated manner.

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Figures

Fig. 1
Fig. 1
(A) Overall structure of the C/EBPα bZIP–DNA complex (PDB code 1NWQ). LZ, leucine zipper; BR, basic region; EBR, extended basic region. (B) The LZ sequence displayed as heptad repeats. Numbering refers to the complete rat C/EBPα protein sequence. Lower-case letters (top line) show positions of leucine zipper residues as they would appear on a standard helical wheel representation of a coiled-coil dimer; “d” corresponds to the position of leucine residues. Coiled-coil structure is stabilized by the van der Waals interactions between residues at a and d positions from both helices and by electrostatic interactions between residues located at g and e positions. (C), The DNA sequence in crystals. Consensus C/EBP recognition site is indicated in blue, and the center of symmetry as a solid circle.
Fig. 2
Fig. 2
DNA recognition. (A) Basic region amino acid sequences and DNA binding sites for representatives of bZIP families. The invariant Asn and Arg are shown in red, conserved basic residues in blue, and the first residue of the leucine zipper is green. Residues that form the KIM motif are marked by asterisks. The cores of the half-sites are underlined. (B), Comparison of conformations of the conserved side chains in the basic regions of C/EBPα (green) and GCN4 (gray). The side chain of the invariant Asn residue from the PAP1 structure is shown in yellow. (Adapted from [77]).
Fig. 3
Fig. 3
Schematic representation of domain organization and predictions of ID regions (referred in various publications) for selected bZIP TFs. Regions predicted as disordered by a variety of prediction programs are marked by colored lines: black, PONDR [97]; dark blue, DISOPRED2 [29]; red, FoldIndex [98]; cyan, Loops/Coil definition; violet, NORSp [100]; magenta, charge-hydrophaty plot [18]. Depicted functionally relevant features are discussed in the text. Boundaries for BR:LZ domain (green) are shown as defined by SMART [102]. Regions necessary for transactivation are shown in orange. δ, and DEF domains contain docking sites for JNK and ERK, respectively. The indicated scale corresponds to the number of amino acids.
Fig. 4
Fig. 4
Mechanism of dimerization specificity for Fos and Jun peptides. (A) A helical wheel diagram of the Fos–Jun coiled-coil. The sequence is read from N to C termini outwards from the wheel. The Fos–Jun heterodimer is stabilized by four electrostatic attractive interactions (solid arrows) and by a hydrogen bond interaction (dashed arrows) between the g and e positions. (B) Potential interactions within homodimer interfaces of Fos and Jun. The formation of Fos homodimer is prevented by four electrostatic repulsive interactions (solid lines). The formation of Jun homodimer is driven by two positive electrostatic interactions and it is additionally stabilized by hydrogen bonds and the interactions between Lys residues (dotted line), wherein the repulsive electrostatic energies between like charges are overcome by the favorable Van der Waals interactions between the methylenes of lysine side chains and hydrophobic amino acids in the a and d positions [85].
Fig. 5
Fig. 5
Conformational flexibility and binding polymorphism of BR from C/EBPs (orange). (A) Structure of C/EBPβ(224–285)–ATF4(280–341) heterodimer in the absence of DNA; (PDB code 1CI6). Note that the entire region corresponding to the C/EBPβ recognition helix is missing. (B) Structure of the classic, bipartite NLS peptide (orange) bound to armadillo domain of importin α (gray); (PDB code 1EJY). (C) Hypothetical interactions of C/EBPα BR peptide with the BRCT domain of BRCA1. Y285 corresponds to Y225 in C/EBPβ. (D) C/EBPβ recognition helix (residues 225-240) bound to cognate DNA (PDB code 1H8A).
Fig. 6
Fig. 6
Possible intermediates in the monomer and dimer pathways during assembly of bZIP–DNA complexes.
Fig. 7
Fig. 7
Protein recognition motifs identified in TADs. (A) Sequence alignment of Box A and B homologies present in C/EBPs. Residues comprising TAF9 binding motif are marked by asterisks. (B) Homology boxes, HOB1 and HOB2, from c-Jun/c-Fos. Identical residues representing consensus and sequence similarities with Box B are highlighted in cyan. (C) KIX binding sequences. Residues contacting KIX are shown in bold print. The conserved phosphorylation motif in KID domains is highlighted in yellow and the critical Leu (see text) is shown in red.
Fig. 8
Fig. 8
Binding commonality and binding diversity displayed by pKID domain of CREB. (A) Synergistic binding of c-MYB (purple) and MLL (green) to KIX (gray); (PDB code 2AGH). (B) pKID (navy) bound to KIX; (PDB code 1KDX). Solvent accessible surface of KIX is shown in gray, Tyr658 in yellow, side chain of phosphorylated Ser133 is represented as balls-and-sticks. (C) Superposition of pKID and c-MYB peptides bound to the same site on KIX (competitive binding). The bend of the α helix of c-Myb facilitates optimal interactions with KIX and enables a critical Leu side chain to penetrate much more deeply than the equivalent Leu from pKID does into the hydrophobic pocket of KIX. (D) Model structure of pKID bound to GSK-3β (beige). The phosphate binding site is depicted in yellow; (adapted from [174]).
Fig. 9
Fig. 9
The NFAT–Fos–Jun–DNA quaternary complex (PDB code 1A02). The ARRE2 DNA sequence in the crystal is shown below the figure. Note the deviation from the consensus sequence (TGAGTCA) recognized by AP-1 proteins. Protein–protein interactions between NFAT and the LZ of AP-1 enable the two TFs to bind DNA cooperatively, and regulate coordinately the IL-2 promoter.
Fig. 10
Fig. 10
The intercomplex interactions between c-Myb bound to one DNA fragment and the C-terminal portions of C/EBPβ homodimer bound to another DNA fragment observed in the crystal structure of the c-Myb–C/EBPβ–DNA complex [188]; PDB code 1H89. The helical fold of C-terminal extensions of C/EBPβ LZ is induced by interaction with c-Myb.
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