1i07 Citations

Effect of pH and salt bridges on structural assembly: molecular structures of the monomer and intertwined dimer of the Eps8 SH3 domain.

Protein Sci. 10 1046-55 (2001)
Cited: 22 times
EuropePMC logo PMID: 11316885

Abstract

The SH3 domain of Eps8 was previously found to form an intertwined, domain-swapped dimer. We report here a monomeric structure of the EPS8 SH3 domain obtained from crystals grown at low pH, as well as an improved domain-swapped dimer structure at 1.8 A resolution. In the domain-swapped dimer the asymmetric unit contains two "hybrid-monomers." In the low pH form there are two independently folded SH3 molecules per asymmetric unit. The formation of intermolecular salt bridges is thought to be the reason for the formation of the dimer. On the basis of the monomer SH3 structure, it is argued that Eps8 SH3 should, in principle, bind to peptides containing a PxxP motif. Recently it was reported that Eps8 SH3 binds to a peptide with a PxxDY motif. Because the "SH3 fold" is conserved, alternate binding sites may be possible for the PxxDY motif to bind. The strand exchange or domain swap occurs at the n-src loops because the n-src loops are flexible. The thermal b-factors also indicate the flexible nature of n-src loops and a possible handle for domain swap initiation. Despite the loop swapping, the typical SH3 fold in both forms is conserved structurally. The interface of the acidic form of SH3 is stabilized by a tetragonal network of water molecules above hydrophobic residues. The intertwined dimer interface is stabilized by hydrophobic and aromatic stacking interactions in the core and by hydrophilic interactions on the surface.

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  1. Frustration in the energy landscapes of multidomain protein misfolding. Zheng W, Schafer NP, Wolynes PG. Proc. Natl. Acad. Sci. U.S.A. 110 1680-1685 (2013)
  2. Structural Determinants of Misfolding in Multidomain Proteins. Tian P, Best RB. PLoS Comput. Biol. 12 e1004933 (2016)


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  1. Novel oncoprotein EPS8: a new target for anticancer therapy. Li YH, Xue TY, He YZ, Du JW. Future Oncol 9 1587-1594 (2013)
  2. Signal transduction in bacterial chemotaxis. Baker MD, Wolanin PM, Stock JB. Bioessays 28 9-22 (2006)
  3. Protein folding and three-dimensional domain swapping: a strained relationship? Newcomer ME. Curr. Opin. Struct. Biol. 12 48-53 (2002)
  4. Evolution of protein structures and functions. Kinch LN, Grishin NV. Curr. Opin. Struct. Biol. 12 400-408 (2002)
  5. Eps8 in the midst of GTPases. Di Fiore PP, Scita G. Int. J. Biochem. Cell Biol. 34 1178-1183 (2002)

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  1. Domain swapping is a consequence of minimal frustration. Yang S, Cho SS, Levy Y, Cheung MS, Levine H, Wolynes PG, Onuchic JN. Proc. Natl. Acad. Sci. U.S.A. 101 13786-13791 (2004)
  2. Structural basis for SH3 domain-mediated high-affinity binding between Mona/Gads and SLP-76. Harkiolaki M, Lewitzky M, Gilbert RJ, Jones EY, Bourette RP, Mouchiroud G, Sondermann H, Moarefi I, Feller SM. EMBO J. 22 2571-2582 (2003)
  3. Topological determinants of protein domain swapping. Ding F, Prutzman KC, Campbell SL, Dokholyan NV. Structure 14 5-14 (2006)
  4. Molecular basis for the dual function of Eps8 on actin dynamics: bundling and capping. Hertzog M, Milanesi F, Hazelwood L, Disanza A, Liu H, Perlade E, Malabarba MG, Pasqualato S, Maiolica A, Confalonieri S, Le Clainche C, Offenhauser N, Block J, Rottner K, Di Fiore PP, Carlier MF, Volkmann N, Hanein D, Scita G. PLoS Biol. 8 e1000387 (2010)
  5. Simple but predictive protein models. Ding F, Dokholyan NV. Trends Biotechnol. 23 450-455 (2005)
  6. Protein oligomerization through domain swapping: role of inter-molecular interactions and protein concentration. Yang S, Levine H, Onuchic JN. J. Mol. Biol. 352 202-211 (2005)
  7. The dual role of a loop with low loop contact distance in folding and domain swapping. Linhananta A, Zhou H, Zhou Y. Protein Sci. 11 1695-1701 (2002)
  8. Detection and characterization of partially unfolded oligomers of the SH3 domain of alpha-spectrin. Casares S, Sadqi M, López-Mayorga O, Conejero-Lara F, van Nuland NA. Biophys. J. 86 2403-2413 (2004)
  9. The 1.1 A resolution crystal structure of the p130cas SH3 domain and ramifications for ligand selectivity. Wisniewska M, Bossenmaier B, Georges G, Hesse F, Dangl M, Künkele KP, Ioannidis I, Huber R, Engh RA. J. Mol. Biol. 347 1005-1014 (2005)
  10. Solution structure of the first SRC homology 3 domain of human Nck2. Park S, Takeuchi K, Wagner G. J. Biomol. NMR 34 203-208 (2006)
  11. Electrostatic effects in the folding of the SH3 domain of the c-Src tyrosine kinase: pH-dependence in 3D-domain swapping and amyloid formation. Bacarizo J, Martinez-Rodriguez S, Martin-Garcia JM, Andujar-Sanchez M, Ortiz-Salmeron E, Neira JL, Camara-Artigas A. PLoS ONE 9 e113224 (2014)
  12. Dimer domain swapping versus monomer folding in apo-myoglobin studied by molecular simulations. Ono K, Ito M, Hirota S, Takada S. Phys Chem Chem Phys 17 5006-5013 (2015)
  13. Fluorescence quenching of (dimethylamino)naphthalene dyes Badan and Prodan by tryptophan in cytochromes P450 and micelles. Pospíšil P, Luxem KE, Ener M, Sýkora J, Kocábová J, Gray HB, Vlček A, Hof M. J Phys Chem B 118 10085-10091 (2014)
  14. Structural study of hNck2 SH3 domain protein in solution by circular dichroism and X-ray solution scattering. Matsumura Y, Shinjo M, Matsui T, Ichimura K, Song J, Kihara H. Biophys. Chem. 175-176 39-46 (2013)
  15. Delineating the role of ionic interactions in structural and functional integrity of B. malayi Guanylate kinase. Gupta S, Suryanarayanan V, Yadav S, Singh SK, Saxena JK. Int. J. Biol. Macromol. 98 357-365 (2017)


Related citations provided by authors (1)

  1. The SH3 Domain of Eps8 Exists as a Novel Intertwined Dimer.. Kishan KV, Scita G, Wong WT, Di Fiore PP, Newcomer ME Nat. Struct. Biol. 4 739-743 (1997)