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Title: Quantifying Intramolecular Binding in Multivalent Interactions: A Structure-Based Synergistic Study on Grb2-Sos1 Complex

Abstract

Numerous signaling proteins use multivalent binding to increase the specificity and affinity of their interactions within the cell. Enhancement arises because the effective binding constant for multivalent binding is larger than the binding constants for each individual interaction. We seek to gain both qualitative and quantitative understanding of the multivalent interactions of an adaptor protein, growth factor receptor bound protein-2 (Grb2), containing two SH3 domains interacting with the nucleotide exchange factor son-of-sevenless 1 (Sos1) containing multiple polyproline motifs separated by flexible unstructured regions. Grb2 mediates the recruitment of Sos1 from the cytosol to the plasma membrane where it activates Ras by inducing the exchange of GDP for GTP. First, using a combination of evolutionary information and binding energy calculations, we predict an additional polyproline motif in Sos1 that binds to the SH3 domains of Grb2. This gives rise to a total of five polyproline motifs in Sos1 that are capable of binding to the two SH3 domains of Grb2. Then, using a hybrid method combining molecular dynamics simulations and polymer models, we estimate the enhancement in local concentration of a polyproline motif on Sos1 near an unbound SH3 domain of Grb2 when its other SH3 domain is bound to amore » different polyproline motif on Sos1. We show that the local concentration of the Sos1 motifs that a Grb2 SH3 domain experiences is approximately 1000 times greater than the cellular concentration of Sos1. Finally, we calculate the intramolecular equilibrium constants for the crosslinking of Grb2 on Sos1 and use thermodynamic modeling to calculate the stoichiometry. With these equilibrium constants, we are able to predict the distribution of complexes that form at physiological concentrations. We believe this is the first systematic analysis that combines sequence, structure, and thermodynamic analyses to determine the stoichiometry of the complexes that are dominant in the cellular environment.« less

Authors:
 [1];  [1];  [1]
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  1. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Publication Date:
Research Org.:
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division; USDOE Laboratory Directed Research and Development (LDRD) Program; National Institutes of Health (NIH)
OSTI Identifier:
1627216
Grant/Contract Number:  
AC52-06NA25396; X9C4; R37-GM035556
Resource Type:
Accepted Manuscript
Journal Name:
PLoS Computational Biology (Online)
Additional Journal Information:
Journal Name: PLoS Computational Biology (Online); Journal Volume: 7; Journal Issue: 10; Journal ID: ISSN 1553-7358
Publisher:
Public Library of Science
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Biochemistry & Molecular Biology; Mathematical & Computational Biology

Citation Formats

Sethi, Anurag, Goldstein, Byron, and Gnanakaran, S. Quantifying Intramolecular Binding in Multivalent Interactions: A Structure-Based Synergistic Study on Grb2-Sos1 Complex. United States: N. p., 2011. Web. doi:10.1371/journal.pcbi.1002192.
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Sethi, Anurag, Goldstein, Byron, & Gnanakaran, S. Quantifying Intramolecular Binding in Multivalent Interactions: A Structure-Based Synergistic Study on Grb2-Sos1 Complex. United States. https://doi.org/10.1371/journal.pcbi.1002192
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Sethi, Anurag, Goldstein, Byron, and Gnanakaran, S. Thu . "Quantifying Intramolecular Binding in Multivalent Interactions: A Structure-Based Synergistic Study on Grb2-Sos1 Complex". United States. https://doi.org/10.1371/journal.pcbi.1002192. https://www.osti.gov/servlets/purl/1627216.
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@article{osti_1627216,
title = {Quantifying Intramolecular Binding in Multivalent Interactions: A Structure-Based Synergistic Study on Grb2-Sos1 Complex},
author = {Sethi, Anurag and Goldstein, Byron and Gnanakaran, S.},
abstractNote = {Numerous signaling proteins use multivalent binding to increase the specificity and affinity of their interactions within the cell. Enhancement arises because the effective binding constant for multivalent binding is larger than the binding constants for each individual interaction. We seek to gain both qualitative and quantitative understanding of the multivalent interactions of an adaptor protein, growth factor receptor bound protein-2 (Grb2), containing two SH3 domains interacting with the nucleotide exchange factor son-of-sevenless 1 (Sos1) containing multiple polyproline motifs separated by flexible unstructured regions. Grb2 mediates the recruitment of Sos1 from the cytosol to the plasma membrane where it activates Ras by inducing the exchange of GDP for GTP. First, using a combination of evolutionary information and binding energy calculations, we predict an additional polyproline motif in Sos1 that binds to the SH3 domains of Grb2. This gives rise to a total of five polyproline motifs in Sos1 that are capable of binding to the two SH3 domains of Grb2. Then, using a hybrid method combining molecular dynamics simulations and polymer models, we estimate the enhancement in local concentration of a polyproline motif on Sos1 near an unbound SH3 domain of Grb2 when its other SH3 domain is bound to a different polyproline motif on Sos1. We show that the local concentration of the Sos1 motifs that a Grb2 SH3 domain experiences is approximately 1000 times greater than the cellular concentration of Sos1. Finally, we calculate the intramolecular equilibrium constants for the crosslinking of Grb2 on Sos1 and use thermodynamic modeling to calculate the stoichiometry. With these equilibrium constants, we are able to predict the distribution of complexes that form at physiological concentrations. We believe this is the first systematic analysis that combines sequence, structure, and thermodynamic analyses to determine the stoichiometry of the complexes that are dominant in the cellular environment.},
doi = {10.1371/journal.pcbi.1002192},
journal = {PLoS Computational Biology (Online)},
number = 10,
volume = 7,
place = {United States},
year = {Thu Oct 13 00:00:00 EDT 2011},
month = {Thu Oct 13 00:00:00 EDT 2011}
}
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Grb2 SH3 binding to peptides from Sos: evaluation of a general model for SH3-ligand interactions
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Aggregation of Membrane Proteins by Cytosolic Cross-Linkers: Theory and Simulation of the LAT-Grb2-SOS1 System
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The Tryptophan Switch: Changing Ligand-binding Specificity from Type I to Type II in SH3 Domains
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Binding Specificity of Multiprotein Signaling Complexes Is Determined by Both Cooperative Interactions and Affinity Preferences †
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SH3 Domains of Grb2 Adaptor Bind to PXψPXR Motifs Within the Sos1 Nucleotide Exchange Factor in a Discriminate Manner
journal, April 2009

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  • Biochemistry, Vol. 48, Issue 19
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Multivalency Effects in Protein−Carbohydrate Interaction:  The Binding of the Shiga-like Toxin 1 Binding Subunit to Multivalent C- Linked Glycopeptides
journal, December 2000

  • Lundquist, Joseph J.; Debenham, Sheryl D.; Toone, Eric J.
  • The Journal of Organic Chemistry, Vol. 65, Issue 24
  • DOI: 10.1021/jo000943e

Oligomerization of signaling complexes by the multipoint binding of GRB2 to both LAT and SOS1
journal, August 2006

  • Houtman, Jon C. D.; Yamaguchi, Hiroshi; Barda-Saad, Mira
  • Nature Structural & Molecular Biology, Vol. 13, Issue 9
  • DOI: 10.1038/nsmb1133

Size, shape, and flexibility of proteins and DNA
journal, October 2009

  • Rawat, Nidhi; Biswas, Parbati
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  • DOI: 10.1063/1.3251769

Evolutionary profiles from the QR factorization of multiple sequence alignments
journal, March 2005

  • Sethi, A.; O'Donoghue, P.; Luthey-Schulten, Z.
  • Proceedings of the National Academy of Sciences, Vol. 102, Issue 11
  • DOI: 10.1073/pnas.0409715102

Specific interactions outside the proline-rich core of two classes of Src homology 3 ligands.
journal, December 1995

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  • Proceedings of the National Academy of Sciences, Vol. 92, Issue 26
  • DOI: 10.1073/pnas.92.26.12408

Distinct ligand preferences of Src homology 3 domains from Src, Yes, Abl, Cortactin, p53bp2, PLCgamma, Crk, and Grb2.
journal, February 1996

  • Sparks, A. B.; Rider, J. E.; Hoffman, N. G.
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Differential Interactions of Human Sos1 and Sos2 with Grb2
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  • Yang, Shao-song; Van Aelst, Linda; Bar-Sagi, Dafna
  • Journal of Biological Chemistry, Vol. 270, Issue 31
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The Grb2-mSos1 Complex Binds Phosphopeptides with Higher Affinity than Grb2
journal, November 1996

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  • Journal of Biological Chemistry, Vol. 271, Issue 48
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High resolution mapping of mast cell membranes reveals primary and secondary domains of FcϵRI and LAT
journal, August 2001

  • Wilson, Bridget S.; Pfeiffer, Janet R.; Surviladze, Zurab
  • Journal of Cell Biology, Vol. 154, Issue 3
  • DOI: 10.1083/jcb.200104049

T cell receptor ligation induces the formation of dynamically regulated signaling assemblies
journal, September 2002

  • Bunnell, Stephen C.; Hong, David I.; Kardon, Julia R.
  • Journal of Cell Biology, Vol. 158, Issue 7
  • DOI: 10.1083/jcb.200203043

CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice
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  • Thompson, Julie D.; Higgins, Desmond G.; Gibson, Toby J.
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An experimental study of GFP-based FRET, with application to intrinsically unstructured proteins
journal, July 2007

  • Ohashi, Tomoo; Galiacy, Stephane D.; Briscoe, Gina
  • Protein Science, Vol. 16, Issue 7
  • DOI: 10.1110/ps.072845607

The Guanine Nucleotide-Binding Switch in Three Dimensions
journal, November 2001

Coupling of Ras and Rac Guanosine Triphosphatases Through the Ras Exchanger Sos
journal, January 1998

Crystal structure of the mammalian Grb2 adaptor
journal, April 1995

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