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Tumor-Suppressor p53TAD^1-60 Forms a Fuzzy Complex with Metastasis-Associated S100A4: Structural Insights and Dynamics by an NMR/MD Approach.

ABSTRACT: Conformationally flexible protein complexes represent a major challenge for structural and dynamical studies. We present herein a method based on a hybrid NMR/MD approach to characterize the complex formed between the disordered p53TAD^1-60 and the metastasis-associated S100A4. Disorder-to-order transitions of both TAD1 and TAD2 subdomains upon interaction is detected. Still, p53TAD^1-60 remains highly flexible in the bound form, with residues L26, M40, and W53 being anchored to identical hydrophobic pockets of the S100A4 monomer chains. In the resulting "fuzzy" complex, the clamp-like binding of p53TAD^1-60 relies on specific hydrophobic anchors and on the existence of extended flexible segments. Our results demonstrate that structural and dynamical NMR parameters (cumulative ??, SSP, temperature coefficients, relaxation time, hetNOE) combined with MD simulations can be used to build a structural model even if, due to high flexibility, the classical solution structure calculation is not possible.

SUBMITTER: Dudas EF

PROVIDER: S-EPMC7689910 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Tumor-Suppressor p53TAD1-60 Forms a Fuzzy Complex with Metastasis-Associated S100A4: Structural Insights and Dynamics by an NMR/MD Approach.

Dudás Erika F EF Pálfy Gyula G Menyhárd Dóra K DK Sebák Fanni F Ecsédi Péter P Nyitray László L Bodor Andrea A

Chembiochem : a European journal of chemical biology 20200722 21

Conformationally flexible protein complexes represent a major challenge for structural and dynamical studies. We present herein a method based on a hybrid NMR/MD approach to characterize the complex formed between the disordered p53TAD1-60 and the metastasis-associated S100A4. Disorder-to-order transitions of both TAD1 and TAD2 subdomains upon interaction is detected. Still, p53TAD1-60 remains highly flexible in the bound form, with residues L26, M40, and W53 being anchored ...[more]

PMID: 32511842

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Project description:Backbone (15N) NMR relaxation is one of the main sources of information on dynamics of disordered proteins. Yet, we do not know very well what drives 15N relaxation in such systems, i.e., how different forms of motion contribute to the measurable relaxation rates. To address this problem, we have investigated, both experimentally and via molecular dynamics simulations, the dynamics of a 26-residue peptide imitating the N-terminal portion of the histone protein H4. One part of the peptide was found to be fully flexible, whereas the other part features some transient structure (a hairpin stabilized by hydrogen bonds). The following motional modes proved relevant for 15N relaxation. 1) Sub-picosecond librations attenuate relaxation rates according to S2 ?0.85-0.90. 2) Axial peptide-plane fluctuations along a stretch of the peptide chain contribute to relaxation-active dynamics on a fast timescale (from tens to hundreds of picoseconds). 3) ?/? backbone jumps contribute to relaxation-active dynamics on both fast (from tens to hundreds of picoseconds) and slow (from hundreds of picoseconds to a nanosecond) timescales. The major contribution is from polyproline II (PPII) ? ? transitions in the Ramachandran space; in the case of glycine residues, the major contribution is from PPII ? (?) ? rPPII transitions, in which rPPII is the mirror-image (right-handed) version of the PPII geometry, whereas ? geometry plays the role of an intermediate state. 4) Reorientational motion of certain (sufficiently long-lived) elements of transient structure, i.e., rotational tumbling, contributes to slow relaxation-active dynamics on ?1-ns timescale (however, it is difficult to isolate this contribution). In conclusion, recent advances in the area of force-field development have made it possible to obtain viable Molecular Dynamics models of protein disorder. After careful validation against the experimental relaxation data, these models can provide a valuable insight into mechanistic origins of spin relaxation in disordered peptides and proteins.

Dataset Information

Tumor-Suppressor p53TAD^1-60 Forms a Fuzzy Complex with Metastasis-Associated S100A4: Structural Insights and Dynamics by an NMR/MD Approach.

Publications

Tumor-Suppressor p53TAD<sup>1-60</sup> Forms a Fuzzy Complex with Metastasis-Associated S100A4: Structural Insights and Dynamics by an NMR/MD Approach.

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