TITLE

Tyr66 acts as a conformational switch in the closed-to-open transition of the SHP-2 N-SH2-domain phosphotyrosine-peptide binding cleft

AUTHOR(S)
Guvench, Olgun; Qu, Cheng-Kui; MacKerell Jr., Alexander D.
PUB. DATE
January 2007
SOURCE
BMC Structural Biology;2007, Vol. 7, p14
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Background: The N-terminal SH2 domain (N-SH2) of the non-receptor tyrosine phosphatase SHP-2 is involved both in localization of SHP-2 by recognition of phosphotyrosine (pY) peptides and self-inhibition of SHP-2 phosphatase activity through the formation of a protein - protein interface with the phosphatase domain. Mutations that disrupt this interface break the coupling between pY-peptide binding cleft conformation and self-inhibition, thereby increasing both SHP-2 phosphatase activity and pY-peptide binding affinity, and are associated with the congenital condition Noonan syndrome and various pediatric leukemias. To better characterize the molecular process involved in N-SH2 pY-dependent binding, we have applied explicit-solvent molecular dynamics simulations to study the closed-to-open transition of the N-SH2 pY-peptide binding cleft. Results: The existence of stable conformations in the left-handed helical and the extended regions of Tyr66 Φ/ψ space prevent rapid interconversion of the backbone and create a conformational switch such that Tyr66 in a left-handed helical backbone conformation results in an open cleft and in an extended backbone conformation results in a closed cleft. The stable conformations arise from deep, well-localized free-energy minima in the left-handed helical and extended regions of the Tyr66 Φ/ψ map. Changing the Tyr66 backbone conformation from extended to left-handed helical induces a closed-to-open transition in the cleft, and the reverse change in backbone conformation induces the reverse, open-to-closed transition. In the open-cleft state, weak solvent-exposed interactions involving the sidechains of Tyr66, Asp40, Lys55, and Gln57 serve to anchor the Tyr66 sidechain to the surface of the protein and away from the binding cleft entrance, thereby facilitating pY-peptide access to the binding cleft. Conclusion: The simulations point to a regulatory role for Tyr66 and surrounding residues in SHP-2 function: mutations at Tyr66, Asp40, Lys55, and/or Gln57 are predicted to break the switching mechanism and negatively impact pY-peptide binding. This in turn would interfere with cellular localization and the coupled SHP-2 phosphatase activity. The structurally well-defined binding cleft conformations resulting from the switch-like transition suggest the possibility of applying structure-based methods to develop inhibitors of N-SH2 pY-peptide binding to serve as research tools for signal transduction and precursors to therapeutics for SHP-2-related diseases.
ACCESSION #
29323587

 

Related Articles

  • Sampling small-scale and large-scale conformational changes in proteins and molecular complexes. Yun, Mi-Ran; Mousseau, N.; Derreumaux, P. // Journal of Chemical Physics;3/14/2007, Vol. 126 Issue 10, p105101 

    Sampling of small-scale and large-scale motions is important in various computational tasks, such as protein-protein docking and ligand binding. Here, we report further development and applications of the activation-relaxation technique for internal coordinate space trajectories (ARTIST). This...

  • Dynamically driven protein allostery. Popovych, Nataliya; Sun, Shangjin; Ebright, Richard H.; Kalodimos, Charalampos G. // Nature Structural & Molecular Biology;Sep2006, Vol. 13 Issue 9, p831 

    Allosteric interactions are typically considered to proceed through a series of discrete changes in bonding interactions that alter the protein conformation. Here we show that allostery can be mediated exclusively by transmitted changes in protein motions. We have characterized the negatively...

  • Inactive and active states and supramolecular organization of GPCRs: insights from computational modeling. Fanelli, Francesca; De Benedetti, Pier G. // Journal of Computer-Aided Molecular Design;Jul2006, Vol. 20 Issue 7/8, p449 

    Herein we make an overview of the results of our computational experiments aimed at gaining insight into the molecular mechanisms of GPCR functioning either in their normal conditions or when hit by gain-of-function or loss-of-function mutations. Molecular simulations of a number of GPCRs in...

  • Ligand Binding and Circular Permutation Modify Residue Interaction Network in DHFR. Hu, Zengjian; Bowen, Donnell; Southerland, William M.; Del Sol, Antonio; Pan, Yongping; Nussinov, Ruth; Ma, Buyong // PLoS Computational Biology;Jun2007, Vol. 3 Issue 6, pe117 

    Residue interaction networks and loop motions are important for catalysis in dihydrofolate reductase (DHFR). Here, we investigate the effects of ligand binding and chain connectivity on network communication in DHFR. We carry out systematic network analysis and molecular dynamics simulations of...

  • A previously unobserved conformation for the human Pex5p receptor suggests roles for intrinsic flexibility and rigid domain motions in ligand binding. Stanley, Will A.; Pursiainen, Niko V.; Garman, Elspeth F.; Juffer, André H.; Wilmanns, Matthias; Kursula, Petri // BMC Structural Biology;2007, Vol. 7, p24 

    Background: The C-terminal tetratricopeptide (TPR) repeat domain of Pex5p recognises proteins carrying a peroxisomal targeting signal type 1 (PTS1) tripeptide in their C-terminus. Previously, structural data have been obtained from the TPR domain of Pex5p in both the liganded and unliganded...

  • Text-mining, milk proteins and nutraceutical potential -- the MilkER project. Edward, Stephen; Webber, Bonnie; Holt, Carl; Sawyer, Lindsay // BMC Bioinformatics;2005 Supplement 3, Vol. 6, p1 

    A conference paper about the Milk Extraction Resource (milkER) database is presented. The database aims to provide information about milk protein and gene sequence, ligand binding, bioactive peptide and protein-protein/disease interaction for many mammalian species. The milkER project also aims...

  • X-ray vision reveals conformational changes. Eisenstein, Michael // Nature Methods;Dec2004, Vol. 1 Issue 3, p188 

    A new study demonstrates that X-ray scattering data can reveal even minor conformational changes induced in a protein after ligand binding, offering a potentially valuable tool to expedite biochemical studies and drug design.

  • Structure and Function in Homodimeric Enzymes: Simulations of Cooperative and Independent Functional Motions. Wells, Stephen A.; van der Kamp, Marc W.; McGeagh, John D.; Mulholland, Adrian J. // PLoS ONE;8/4/2015, Vol. 10 Issue 8, p1 

    Large-scale conformational change is a common feature in the catalytic cycles of enzymes. Many enzymes function as homodimers with active sites that contain elements from both chains. Symmetric and anti-symmetric cooperative motions in homodimers can potentially lead to correlated active site...

  • The Role of Flexibility and Conformational Selection in the Binding Promiscuity of PDZ Domains. Münz, Márton; Hein, Jotun; Biggin, Philip C. // PLoS Computational Biology;Nov2012, Vol. 8 Issue 11, p1 

    In molecular recognition, it is often the case that ligand binding is coupled to conformational change in one or both of the binding partners. Two hypotheses describe the limiting cases involved; the first is the induced fit and the second is the conformational selection model. The...

Share

Read the Article

Courtesy of VIRGINIA BEACH PUBLIC LIBRARY AND SYSTEM

Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics