Structure-based Prediction of bZIP Partnering Specificity

Grigoryan, Gevorg; Keating, Amy E.

doi:10.1016/j.jmb.2005.11.036

Cited by 64 publications

(88 citation statements)

References 90 publications

(124 reference statements)

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“…For these reasons, the dimerization properties of LZ-containing TFs have been a subject of extensive investigation. Analysis of available crystal and solution structures [113], molecular modeling [114] and mutagenesis studies [84] has helped to establish sets of rules, which make it possible to predict interaction preferences for bZIP peptides with great precision [85,112,115] Dimerization selectivity depends on the "complementarity" of the putative partners, which is defined by the precise distribution of hydrophilic and hydrophobic residues in the LZ regions. The dimer interface is formed by the residues located at the a, d, e, and g positions of the (abcdefg)n heptad repeat (see Fig.…”

Section: Dimerization Specificitymentioning

confidence: 99%

The Importance of Being Flexible: The Case of Basic Region Leucine Zipper Transcriptional Regulators

2013

Advances in Protein and Peptide Sciences

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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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Section: Dimerization Specificitymentioning

confidence: 99%

The Importance of Being Flexible: The Case of Basic Region Leucine Zipper Transcriptional Regulators

2013

Advances in Protein and Peptide Sciences

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“…[13][14][15] For dimeric coiled coils, the supercoil values used in this study are as follows: R cc 5 4.3 Å (supercoil radius), u 5 218 (starting helical phase), and x 5 98 amino acids/ turn (supercoil frequency), where we intentionally used an R cc value smaller than is common for native coiled-coil dimers to be sure that challenging repulsive energy terms were included in CE fitting. 16 For trimeric coiled coils, the supercoil values R cc 5 6.35 Å , u 5 178, and x 5 106 amino acids/turn were used, where these values were obtained by analyzing eight crystal structures (PDB entries 1afd, 1zim, 1ij0, 1ij2, 1ij3, 1ce0, 2akf, and 1b08). Using these parameters, backbone models for parallel coiled coils with 35 residues per a-helix were generated that started with heptad position c and ended with position b five heptads later (Figs.…”

Section: Coiled-coil Modelsmentioning

confidence: 99%

Identifying and reducing error in cluster‐expansion approximations of protein energies

et al. 2010

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Protein design involves searching a vast space for sequences that are compatible with a defined structure. This can pose significant computational challenges. Cluster expansion is a technique that can accelerate the evaluation of protein energies by generating a simple functional relationship between sequence and energy. The method consists of several steps. First, for a given protein structure, a training set of sequences with known energies is generated. Next, this training set is used to expand energy as a function of clusters consisting of single residues, residue pairs, and higher order terms, if required. The accuracy of the sequence-based expansion is monitored and improved using cross-validation testing and iterative inclusion of additional clusters. As a trade-off for evaluation speed, the cluster-expansion approximation causes prediction errors, which can be reduced by including more training sequences, including higher order terms in the expansion, and/or reducing the sequence space described by the cluster expansion. This article analyzes the sources of error and introduces a method whereby accuracy can be improved by judiciously reducing the described sequence space. The method is applied to describe the sequence-stability relationship for several protein structures: coiled-coil dimers and trimers, a PDZ domain, and T4 lysozyme as examples with computationally derived energies, and SH3 domains in amphiphysin-1 and endophilin-1 as examples where the expanded pseudo-energies are obtained from experiments. Our open-source software package Cluster Expansion Version 1.0 allows users to expand their own energy function of interest and thereby apply cluster expansion to custom problems in protein design.

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“…Indeed, substantial progress has been made toward predicting the specificity of coiled-coil interactions from additive predictions based on model leucine zippers. [20][21][22] However, assembly of globular dimers appears to be very different. Comparison of the contact profiles for OxyR and CynR, the two LTTRs we have so far studied in detail, shows that while much of the same surface is used in regulatory domain dimerization, the majority of the residue-residue interactions are different reflecting a difference in rotation of the monomers along the plane of the interaction surface [ Fig.…”

Section: Knapp and Humentioning

confidence: 99%

The oligomerization of CynR in Escherichia coli

Knapp

Tsai

2009

Protein Science

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Deletion analysis and alanine-scanning based on a homology-based interaction model were used to identify determinants of oligomerization in the transcriptional regulator CynR, a member of the LysR-type transcriptional regulator (LTTR) family. Deletion analysis confirmed that the putative regulatory domain of CynR was essential for driving the oligomerization of k repressor-CynR fusion proteins. The interaction surface of a different LTTR and OxyR was mapped onto a multiple sequence alignment of the LTTR family. This mapping identified putative contacts in the CynR regulatory domain dimer interface, which were targeted for alanine-scanning mutagenesis. Oligomerization was assayed by the ability of mutant k repressor-CynR fusions to assemble in E. coli revealing interesting similarities and differences between OxyR and CynR.

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Structure-based Prediction of bZIP Partnering Specificity

Cited by 64 publications

References 90 publications

The Importance of Being Flexible: The Case of Basic Region Leucine Zipper Transcriptional Regulators

The Importance of Being Flexible: The Case of Basic Region Leucine Zipper Transcriptional Regulators

Identifying and reducing error in cluster‐expansion approximations of protein energies

The oligomerization of CynR in Escherichia coli

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