A modular approach to map out the conformational landscapes of unbound intrinsically disordered proteins

Luong, Thinh; Nagpal, Suhani; Sadqi, Mourad; Muñoz, Víctor

doi:10.1073/pnas.2113572119

Cited by 9 publications

(5 citation statements)

References 63 publications

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“…On the contrary, Cluster 2 (purple) is the most compact overall, while the other two clusters (3-brown, 4-magenta) have complementary distance maps, with a mixture of expansion and compaction compared to the full ensemble. Motivated by the growing literature on the binding mechanisms of IDPs − and the expansion we previously captured between residues 32–91 and 73–121 of NP 4E-BP2 upon binding to eIF4E, we asked whether the expanded clusters were conformationally similar to bound-state structures.…”

Section: Resultsmentioning

confidence: 99%

Delineating Structural Propensities of the 4E-BP2 Protein via Integrative Modeling and Clustering

Tsangaris,

Smyth,

Gomes

et al. 2023

J. Phys. Chem. B

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The intrinsically disordered 4E-BP2 protein regulates mRNA cap-dependent translation through interaction with the predominantly folded eukaryotic initiation factor 4E (eIF4E). Phosphorylation of 4E-BP2 dramatically reduces the level of eIF4E binding, in part by stabilizing a binding-incompatible folded domain. Here, we used a Rosetta-based sampling algorithm optimized for IDRs to generate initial ensembles for two phospho forms of 4E-BP2, non- and 5-fold phosphorylated (NP and 5P, respectively), with the 5P folded domain flanked by N- and C-terminal IDRs (N-IDR and C-IDR, respectively). We then applied an integrative Bayesian approach to obtain NP and 5P conformational ensembles that agree with experimental data from nuclear magnetic resonance, small-angle X-ray scattering, and single-molecule Förster resonance energy transfer (smFRET). For the NP state, inter-residue distance scaling and 2D maps revealed the role of charge segregation and pi interactions in driving contacts between distal regions of the chain (∼70 residues apart). The 5P ensemble shows prominent contacts of the N-IDR region with the two phosphosites in the folded domain, pT37 and pT46, and, to a lesser extent, delocalized interactions with the C-IDR region. Agglomerative hierarchical clustering led to partitioning of each of the two ensembles into four clusters with different global dimensions and contact maps. This helped delineate an NP cluster that, based on our smFRET data, is compatible with the eIF4E-bound state. 5P clusters were differentiated by interactions of C-IDR with the folded domain and of the N-IDR with the two phosphosites in the folded domain. Our study provides both a better visualization of fundamental structural poses of 4E-BP2 and a set of falsifiable insights on intrachain interactions that bias folding and binding of this protein.

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Section: Resultsmentioning

confidence: 99%

Delineating Structural Propensities of the 4E-BP2 Protein via Integrative Modeling and Clustering

Tsangaris,

Smyth,

Gomes

et al. 2023

J. Phys. Chem. B

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“…It is likely that the intrinsic disorder permits KID to bind partners via either conformational selection (fold first and then bind) [ 16 ] or induced-fit (bind first and fold while bound) [ 52 ] processes or alternating between conformational selection and induced fit [ 53 ]. Moreover, to fold upon binding as a conformational switch, KID sequences must fully encode all the structures they form in complex with diverse partners.…”

Section: Discussionmentioning

confidence: 99%

“…It was recognised that modules consist of groups of highly cooperative residues [ 2 , 13 ], which may possess certain functional independence. Usually, protein modules are interconnected through amino acids that maintain the shortest pathways between all amino acids and are, thus, crucial for signal transmission, leading to robust and efficient communication networks [ 4 , 8 , 14 , 15 , 16 ]. This modular organisation is advantageous and, as such, has been conserved in its improved version.…”

Section: Introductionmentioning

confidence: 99%

Does Generic Cyclic Kinase Insert Domain of Receptor Tyrosine Kinase KIT Clone Its Native Homologue?

Ledoux

Tchertanov

2022

IJMS

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Receptor tyrosine kinases (RTKs) are modular membrane proteins possessing both well-folded and disordered domains acting together in ligand-induced activation and regulation of post-transduction processes that tightly couple extracellular and cytoplasmic events. They ensure the fine-turning control of signal transmission by signal transduction. Deregulation of RTK KIT, including overexpression and gain of function mutations, has been detected in several human cancers. In this paper, we analysed by in silico techniques the Kinase Insert Domain (KID), a key platform of KIT transduction processes, as a generic macrocycle (KIDGC), a cleaved isolated polypeptide (KIDC), and a natively fused TKD domain (KIDD). We assumed that these KID species have similar structural and dynamic characteristics indicating the intrinsically disordered nature of this domain. This finding means that both polypeptides, cyclic KIDGC and linear KIDC, are valid models of KID integrated into the RTK KIT and will be helpful for further computational and empirical studies of post-transduction KIT events.

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“…To search for the corresponding conformations of the molecule, systematic and stochastic search methods are used. These methods give variations in structural parameters (angles and bond lengths), gradually revealing the appropriate conformation [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Nature of Luminescence and Pharmacological Activity of Sulfaguanidine

et al. 2023

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Sulfonamides are one of the oldest groups of veterinary chemotherapeutic agents. Physico-chemical properties, the concentration and the nature of the environment are the factors responsible for the distribution of sulfonamides in the living organism. Although these drug compounds have been in use for more than half a century, knowledge about their behavior is still limited. Physiological activity is currently attributed to the sulfanyl radical. Our study is devoted to the spectral properties of aqueous solutions of sulfaguanidine, in which the formation of complexes with an H-bond and a protonated form takes place. The nature of the fluorescent state of sulfaguanidine was interpreted using computational chemistry, the electronic absorption method and the luminescence method. The structure of sulfaguanidine includes several active fragments: aniline, sulfonic and guanidine. To reveal the role of fragments in the physiological activity of the studied antibiotic, we calculated and compared the effective charges of the fragments of aniline and sulfaguanidine molecules. Chromophore groups were identified in molecules, which determine the intermolecular interaction between a molecule and a proton-donor solvent. The study also revealed the impact of sulfone and guanidine groups, as well as complexation, on the effective charge of the antibiotic fragment responsible for physiological activity and luminescent ability.

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A modular approach to map out the conformational landscapes of unbound intrinsically disordered proteins

Cited by 9 publications

References 63 publications

Delineating Structural Propensities of the 4E-BP2 Protein via Integrative Modeling and Clustering

Delineating Structural Propensities of the 4E-BP2 Protein via Integrative Modeling and Clustering

Does Generic Cyclic Kinase Insert Domain of Receptor Tyrosine Kinase KIT Clone Its Native Homologue?

Nature of Luminescence and Pharmacological Activity of Sulfaguanidine

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