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Molecular details of Itk activation by prolyl isomerization and phospholigand binding: the NMR structure of the Itk SH2 domain bound to a phosphopeptide.

J. Mol. Biol. 357 550-61 (2006)
Related entries: 1lum, 1lun, 2etz, 1lui, 1luk

Cited: 30 times
EuropePMC logo PMID: 16436281

Abstract

The Src homology 2 (SH2) domain of interleukin-2 tyrosine kinase (Itk) is a critical component of the regulatory apparatus controlling the activity of this immunologically important enzyme. To gain insight into the structural features associated with the activated form of Itk, we have solved the NMR structure of the SH2 domain bound to a phosphotyrosine-containing peptide (pY) and analyzed changes in trans-hydrogen bond scalar couplings ((3h)J(NC')) that result from pY binding. Isomerization of a single prolyl imide bond in this domain is responsible for simultaneous existence of two distinct SH2 conformers. Prolyl isomerization directs ligand recognition: the trans conformer preferentially binds pY. The structure of the SH2/pY complex provides insight into the ligand specificity; the BG loop in the ligand-free trans SH2 conformer is pre-arranged for optimal contacts with the pY+3 residue of the ligand. Analysis of (3h)J(NC') couplings arising from hydrogen bonds has revealed propagation of structural changes from the pY binding pocket to the CD loop containing conformationally heterogeneous proline as well as to the alphaB helix, on the opposite site of the domain. These findings offer a structural framework for understanding the roles of prolyl isomerization and pY binding in Itk regulation.

Reviews citing this publication (12)

  1. T cell activation. Smith-Garvin JE, Koretzky GA, Jordan MS. Annu. Rev. Immunol. 27 591-619 (2009)
  2. Prolyl cis-trans isomerization as a molecular timer. Lu KP, Finn G, Lee TH, Nicholson LK. Nat. Chem. Biol. 3 619-629 (2007)
  3. The Src, Syk, and Tec family kinases: distinct types of molecular switches. Bradshaw JM. Cell. Signal. 22 1175-1184 (2010)
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  5. A new twist to adaptor proteins contributes to regulation of lymphocyte cell signaling. Isakov N. Trends Immunol. 29 388-396 (2008)
  6. Experimental detection of short regulatory motifs in eukaryotic proteins: tips for good practice as well as for bad. Gibson TJ, Dinkel H, Van Roey K, Diella F. Cell Commun. Signal 13 42 (2015)
  7. Experimental detection of short regulatory motifs in eukaryotic proteins: tips for good practice as well as for bad. Gibson TJ, Dinkel H, Van Roey K, Diella F. Cell Commun. Signal 13 42 (2015)
  8. The Src, Syk, and Tec family kinases: distinct types of molecular switches. Bradshaw JM. Cell. Signal. 22 1175-1184 (2010)
  9. T cell activation. Smith-Garvin JE, Koretzky GA, Jordan MS. Annu. Rev. Immunol. 27 591-619 (2009)
  10. ITK inhibitors in inflammation and immune-mediated disorders. Sahu N, August A. Curr Top Med Chem 9 690-703 (2009)
  11. A new twist to adaptor proteins contributes to regulation of lymphocyte cell signaling. Isakov N. Trends Immunol. 29 388-396 (2008)
  12. Prolyl cis-trans isomerization as a molecular timer. Lu KP, Finn G, Lee TH, Nicholson LK. Nat. Chem. Biol. 3 619-629 (2007)

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  2. Proline cis-trans isomerization controls autoinhibition of a signaling protein. Sarkar P, Reichman C, Saleh T, Birge RB, Kalodimos CG. Mol. Cell 25 413-426 (2007)
  3. Complementation in trans of altered thymocyte development in mice expressing mutant forms of the adaptor molecule SLP76. Jordan MS, Smith JE, Burns JC, Austin JE, Nichols KE, Aschenbrenner AC, Koretzky GA. Immunity 28 359-369 (2008)
  4. Proline isomerization preorganizes the Itk SH2 domain for binding to the Itk SH3 domain. Severin A, Joseph RE, Boyken S, Fulton DB, Andreotti AH. J. Mol. Biol. 387 726-743 (2009)
  5. Evolving specificity from variability for protein interaction domains. Kaneko T, Sidhu SS, Li SS. Trends Biochem. Sci. 36 183-190 (2011)
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  7. A proposed signaling motif for nuclear import in mRNA processing via the formation of arginine claw. Hamelberg D, Shen T, McCammon JA. Proc. Natl. Acad. Sci. U.S.A. 104 14947-14951 (2007)
  8. Conformational snapshots of Tec kinases during signaling. Joseph RE, Andreotti AH. Immunol. Rev. 228 74-92 (2009)
  9. Multigram solution-phase synthesis of three diastereomeric tripeptidic second-generation dendrons based on (2S,4S)-, (2S,4R)-, and (2R,4S)-4-aminoprolines. Zhang A, Schlüter AD. Chem Asian J 2 1540-1548 (2007)
  10. SH2-dependent autophosphorylation within the Tec family kinase Itk. Joseph RE, Severin A, Min L, Fulton DB, Andreotti AH. J. Mol. Biol. 391 164-177 (2009)
  11. Initiation of phage infection by partial unfolding and prolyl isomerization. Hoffmann-Thoms S, Weininger U, Eckert B, Jakob RP, Koch JR, Balbach J, Schmid FX. J. Biol. Chem. 288 12979-12991 (2013)
  12. An essential role for Pin1 in Xenopus laevis embryonic development revealed by specific inhibitors. Wildemann D, Hernandez Alvarez B, Stoller G, Zhou XZ, Lu KP, Erdmann F, Ferrari D, Fischer G. Biol. Chem. 388 1103-1111 (2007)
  13. The cytoplasmic cyclophilin from Azotobacter vinelandii interacts with phosphate acetyltransferase isoforms enhancing their in vitro activity. Dimou M, Venieraki A, Zografou C, Katinakis P. Mol. Biol. Rep. 39 4135-4143 (2012)
  14. Purification, crystallization and preliminary crystallographic analysis of the SH2 domain of IL-2-inducible T-cell kinase. Joseph RE, Ginder ND, Hoy JA, Nix JC, Honzatko RB, Andreotti AH. Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 67 269-273 (2011)
  15. Structure of the interleukin-2 tyrosine kinase Src homology 2 domain; comparison between X-ray and NMR-derived structures. Joseph RE, Ginder ND, Hoy JA, Nix JC, Fulton DB, Honzatko RB, Andreotti AH. Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 68 145-153 (2012)
  16. Insights into structure and function of SHIP2-SH2: homology modeling, docking, and molecular dynamics study. Saqib U, Siddiqi MI. J Chem Biol 4 149-158 (2011)
  17. Control of cytochrome c redox reactivity through off-pathway modifications in the protein hydrogen-bonding network. Gu J, Yang S, Rajic AJ, Kurnikov IV, Prytkova TR, Pletneva EV. Chem. Commun. (Camb.) 50 5355-5357 (2014)
  18. Structure and function of Tec family kinase Itk. Qi Q, Kannan AK, August A. Biomol Concepts 2 223-232 (2011)


Related citations provided by authors (1)

  1. Structural characterization of a proline-driven conformational switch within the Itk SH2 domain.. Mallis RJ, Brazin KN, Fulton DB, Andreotti AH Nat. Struct. Biol. 9 900-5 (2002)