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Antagonism between binding site affinity and conformational dynamics tunes alternative cis-interactions within Shp2.

ABSTRACT: Protein functions are largely affected by their conformations. This is exemplified in proteins containing modular domains. However, the evolutionary dynamics that define and adapt the conformation of such modular proteins remain elusive. Here we show that cis-interactions between the C-terminal phosphotyrosines and SH2 domain within the protein tyrosine phosphatase Shp2 can be tuned by an adaptor protein, Grb2. The competitiveness of two phosphotyrosines, namely pY542 and pY580, for cis-interaction with the same SH2 domain is governed by an antagonistic combination of contextual amino acid sequence and position of the phosphotyrosines. Specifically, pY580 with the combination of a favourable position and an adverse sequence has an overall advantage over pY542. Swapping the sequences of pY542 and pY580 results in one dominant form of cis-interaction and subsequently inhibits the trans-regulation by Grb2. Thus, the antagonistic combination of sequence and position may serve as a basic design principle for proteins with tunable conformations.

SUBMITTER: Sun J

PROVIDER: S-EPMC3777412 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Antagonism between binding site affinity and conformational dynamics tunes alternative cis-interactions within Shp2.

Sun Jie J Lu Shaoying S Ouyang Mingxing M Lin Li-Jung LJ Zhuo Yue Y Liu Bo B Chien Shu S Neel Benjamin G BG Wang Yingxiao Y

Nature communications 20130101

Protein functions are largely affected by their conformations. This is exemplified in proteins containing modular domains. However, the evolutionary dynamics that define and adapt the conformation of such modular proteins remain elusive. Here we show that cis-interactions between the C-terminal phosphotyrosines and SH2 domain within the protein tyrosine phosphatase Shp2 can be tuned by an adaptor protein, Grb2. The competitiveness of two phosphotyrosines, namely pY542 and pY580, for cis-interact ...[more]

PMID: 23792876

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Project description:Isoreticular metal organic frameworks (IRMOFs) have shown high uptake capabilities for storage of H₂ (11.5 wt % at 77 K and 170 bar). A significant literature has employed fragment models and a single adsorbed H₂ to identify adsorption sites within IRMOFs, as well as the necessary adsorbate-adsorbent interactions needed to reach sufficient adsorption enthalpy for practical usage, however at high pressures it remains to be seen if H₂···H₂ intermolecular interactions may influence the energetics. This study focuses upon IRMOF-1 (also known as MOF-5), and examines the individual H₂ stabilization energies at different sites using Möller-Plesset perturbation theory and density functional theory alongside chemical models that consist of isolated fragment models and a cubic super cell cluster consisting of both the face- and edge-cube's of IRMOF-1. Optimization of twenty stable configurations of singly adsorbed H₂ in the super-cell cluster is observed to be essential to obtain energy ordering of the five primary sites consistent with experiment and prior benchmark calculations (α >> β > γ > δ ≈ ε). To examine site-to-site interactions that may occur in the high-pressure regime, 64 co-adsorbed H₂ within a super-cell cluster have been studied (a theoretical maximum of all adsorption sites, 14 wt %). There, delocalization and/or charge transfer of electrons is observed from the σ orbitals of the H₂ bound at the γ positions into the σ* orbitals of H₂ bound at the α sites leads to stabilization of the interaction of H₂ at the γ, by 1.4 kJ/mol, respectively (using M06-2X/LANL2DZ). This effect has been confirmed to be charge transfer, and not a manifestation of enhanced dispersion at high loading, through natural bond order (NBO) analysis and by comparisons of the square of off-diagonal NBO Fock matrix elements for both density functionals that account for dispersion interactions and Hartree-Fock calculations that ignore dispersion.

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Antagonism between binding site affinity and conformational dynamics tunes alternative cis-interactions within Shp2.

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Antagonism between binding site affinity and conformational dynamics tunes alternative cis-interactions within Shp2.

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