The current version of the human immunome network consists of nearly 1400 interactions involving approximately 600 proteins. Intermolecular interactions mediated by proline-rich motifs (PRMs) are observed in many facets of the immune response. The proline-rich regions are known to preferentially adopt a polyproline type II helical conformation, an extended structure that facilitates transient intermolecular interactions such as signal transduction, antigen recognition, cell-cell communication and cytoskeletal organization. The propensity of both the side chain and the backbone carbonyls of the polyproline type II helix to participate in the interface interaction makes it an excellent recognition motif. An advantage of such distinct chemical features is that the interactions can be discriminatory even in the absence of high affinities. Indeed, the immune response is mediated by well-orchestrated low-affinity short-duration intermolecular interactions. The proline-rich regions are predominantly localized in the solvent-exposed regions such as the loops, intrinsically disordered regions, or between domains that constitute the intermolecular interface. Peptide mimics of the PRM have been suggested as potential antagonists of intermolecular interactions. In this paper, we discuss novel PRM-mediated interactions in the human immunome that potentially serve as attractive targets for immunomodulation and drug development for inflammatory and autoimmune pathologies. 1. Protein-Protein Interactions Protein-protein interactions (PPIs) are critical for most biological functions and cellular processes [1, 2]. Under appropriate environmental conditions, the PPIs take place through an interface governed by shape, chemical complementarity, and flexibility of the interacting molecules. Different types of PPIs have been described. Homo- or heterologous oligomeric PPI complexes represent isologous or heterologous association of identical protein units. PPI complexes of interdependent protomer units are referred to as obligate complexes as opposed to nonobligate complexes that occur independently [3, 4]. The strength of PPI is represented by the dissociation constant (KD) expressed in molar concentration and derived from the ratio between the dissociation and association rate constants. Based on duration and affinity, PPIs can be classified as strong interactions that exhibit KD values with μM concentrations and weak or transient interactions with values in the mM or higher concentrations. Transient PPIs are further divided into strong and weak transient interactions.
References
[1]
T. Pawson and P. Nash, “Assembly of cell regulatory systems through protein interaction domains,” Science, vol. 300, no. 5618, pp. 445–452, 2003.
[2]
L. O. Sillerud and R. S. Larson, “Design and structure of peptide and peptidomimetic antagonists of protein-protein interaction,” Current Protein and Peptide Science, vol. 6, no. 2, pp. 151–169, 2005.
[3]
O. Keskin, A. Gursoy, B. Ma, and R. Nussinov, “Towards drugs targeting multiple proteins in a systems biology approach,” Current Topics in Medicinal Chemistry, vol. 7, no. 10, pp. 943–951, 2007.
[4]
I. M. A. Nooren and J. M. Thornton, “Diversity of protein-protein interactions,” EMBO Journal, vol. 22, no. 14, pp. 3486–3492, 2003.
[5]
S. E. Ozbabacan, H. B. Engin, A. Gursoy, and O. Keskin, “Transient protein-protein interactions,” Protein Engineering Design Selection, vol. 24, pp. 635–648, 2011.
[6]
S. Ren, V. N. Uversky, Z. Chen, A. K. Dunker, and Z. Obradovic, “Short Linear Motifs recognized by SH2, SH3 and Ser/Thr Kinase domains are conserved in disordered protein regions,” BMC Genomics, vol. 9, no. 2, article S26, 2008.
[7]
P. Tompa, M. Fuxreiter, C. J. Oldfield, I. Simon, A. K. Dunker, and V. N. Uversky, “Close encounters of the third kind: disordered domains and the interactions of proteins,” BioEssays, vol. 31, no. 3, pp. 328–335, 2009.
[8]
R. Jothi, P. F. Cherukuri, A. Tasneem, and T. M. Przytycka, “Co-evolutionary analysis of domains in interacting proteins reveals insights into domain-domain interactions mediating protein-protein interactions,” Journal of Molecular Biology, vol. 362, no. 4, pp. 861–875, 2006.
[9]
A. Stein, R. B. Russell, and P. Aloy, “3did: interacting protein domains of known three-dimensional structure,” Nucleic Acids Research, vol. 33, pp. D413–D417, 2005.
[10]
A. Zucconi, S. Panni, S. Paoluzi, L. Castagnoli, L. Dente, and G. Cesareni, “Domain repertoires as a tool to derive protein recognition rules,” FEBS Letters, vol. 480, no. 1, pp. 49–54, 2000.
[11]
R. R. Copley, T. Doerks, I. Letunic, and P. Bork, “Protein domain analysis in the era of complete genomes,” FEBS Letters, vol. 513, no. 1, pp. 129–134, 2002.
[12]
F. C. Peterson and B. F. Volkman, “Diversity of polyproline recognition by EVH1 domains,” Frontiers in Bioscience, vol. 14, pp. 833–846, 2009.
[13]
N. E. Davey, N. J. Haslam, D. C. Shields, and R. J. Edwards, “SLiMSearch 2.0: biological context for short linear motifs in proteins,” Nucleic Acids Research, vol. 39, supplement 2, pp. W56–W60, 2011.
[14]
N. E. Davey, K. Van Roey, R. J. Weatheritt et al., “Attributes of short linear motifs,” Molecular BioSystems, vol. 8, no. 1, pp. 268–281, 2012.
[15]
A. Mohan, C. J. Oldfield, P. Radivojac et al., “Analysis of molecular recognition features (MoRFs),” Journal of Molecular Biology, vol. 362, no. 5, pp. 1043–1059, 2006.
[16]
V. Neduva and R. B. Russell, “DILIMOT: discovery of linear motifs in proteins,” Nucleic Acids Research, vol. 34, pp. W350–W355, 2006.
[17]
J. C. Obenauer, L. C. Cantley, and M. B. Yaffe, “Scansite 2.0: proteome-wide prediction of cell signalling interactions using short sequence motifs,” Nucleic Acids Research, vol. 31, no. 13, pp. 3635–3641, 2003.
[18]
V. Vacic, C. J. Oldfield, A. Mohan et al., “Characterization of molecular recognition features, MoRFs, and their binding partners,” Journal of Proteome Research, vol. 6, no. 6, pp. 2351–2366, 2007.
[19]
M. B. Yaffe and L. C. Cantley, “Mapping specificity determinants for protein-protein association using protein fusions and random peptide libraries,” Methods in Enzymology, vol. 328, pp. 157–170, 2000.
[20]
V. Neduva and R. B. Russell, “Peptides mediating interaction networks: new leads at last,” Current Opinion in Biotechnology, vol. 17, no. 5, pp. 465–471, 2006.
[21]
Y. Cheng, C. J. Oldfield, J. Meng, P. Romero, V. N. Uversky, and A. K. Dunker, “Mining α-helix-forming molecular recognition features with cross species sequence alignments,” Biochemistry, vol. 46, no. 47, pp. 13468–13477, 2007.
[22]
A. Stein and P. Aloy, “Contextual specificity in peptide-mediated protein interactions,” PLoS ONE, vol. 3, no. 7, Article ID e2524, 2008.
[23]
E. Petsalaki, A. Stark, E. García-Urdiales, and R. B. Russell, “Accurate prediction of peptide binding sites on protein surfaces,” PLoS Computational Biology, vol. 5, no. 3, Article ID e1000335, 2009.
[24]
C. Chica, F. Diella, and T. J. Gibson, “Evidence for the concerted evolution between short linear protein motifs and their flanking regions,” PloS ONE, vol. 4, no. 7, Article ID e6052, 2009.
[25]
M. Fuxreiter, P. Tompa, and I. Simon, “Local structural disorder imparts plasticity on linear motifs,” Bioinformatics, vol. 23, no. 8, pp. 950–956, 2007.
[26]
A. K. Dunker, M. S. Cortese, P. Romero, L. M. Iakoucheva, and V. N. Uversky, “Flexible nets: the roles of intrinsic disorder in protein interaction networks,” FEBS Journal, vol. 272, no. 20, pp. 5129–5148, 2005.
[27]
P. Romero, Z. Obradovic, X. Li, E. C. Garner, C. J. Brown, and A. K. Dunker, “Sequence complexity of disordered protein,” Proteins, vol. 42, no. 1, pp. 38–48, 2001.
[28]
A. Via, C. M. Gould, C. Gemünd, T. J. Gibson, and M. Helmer-Citterich, “A structure filter for the Eukaryotic Linear Motif Resource,” BMC Bioinformatics, vol. 10, article 351, 2009.
[29]
L. J. Ball, R. Kühne, J. Schneider-Mergener, and H. Oschkinat, “Recognition of proline-rich motifs by protein-protein-interaction domains,” Angewandte Chemie, vol. 44, no. 19, pp. 2852–2869, 2005.
[30]
M. P. Williamson, “The structure and function of proline-rich regions in proteins,” Biochemical Journal, vol. 297, no. 2, pp. 249–260, 1994.
[31]
P. Van der Merwe and A. N. Barclay, “Transient intercellular adhesion: the importance of weak protein-protein interactions,” Trends in Biochemical Sciences, vol. 19, no. 9, pp. 354–358, 1994.
[32]
W. J. Wedemeyer, E. Welker, and H. A. Scheraga, “Proline cis-trans isomerization and protein folding,” Biochemistry, vol. 41, no. 50, pp. 14637–14644, 2002.
[33]
A. A. Adzhubei and M. J. E. Sternberg, “Left-handed polyproline II helices commonly occur in globular proteins,” Journal of Molecular Biology, vol. 229, no. 2, pp. 472–493, 1993.
[34]
A. A. Adzhubei and M. J. E. Sternberg, “Conservation of polyproline II helices in homologous proteins: implications for structure prediction by model building,” Protein Science, vol. 3, no. 12, pp. 2395–2410, 1994.
[35]
M. A. Kelly, B. W. Chellgren, A. L. Rucker et al., “Host-Guest study of left-handed polyproline II helix formation,” Biochemistry, vol. 40, no. 48, pp. 14376–14383, 2001.
[36]
B. J. Stapley and T. P. Creamer, “A survey of left-handed polyproline II helices,” Protein Science, vol. 8, no. 3, pp. 587–595, 1999.
[37]
M. V. Cubellis, F. Caillez, T. L. Blundell, and S. C. Lovell, “Properties of polyproline II, a secondary structure element implicated in protein-protein interactions,” Proteins, vol. 58, no. 4, pp. 880–892, 2005.
[38]
B. K. Kay, M. P. Williamson, and M. Sudol, “The importance of being proline: the interaction of proline-rich motifs in signaling proteins with their cognate domains,” FASEB Journal, vol. 14, no. 2, pp. 231–241, 2000.
[39]
J. F. Gibrat, B. Robson, and J. Garnier, “Influence of the local amino acid sequence upon the zones of the torsional angles φ and ψ adopted by residues in proteins,” Biochemistry, vol. 30, no. 6, pp. 1578–1586, 1991.
[40]
A. Rath, A. R. Davidson, and C. M. Deber, “The structure of "unstructured" regions in peptides and proteins: role of the polyproline II helix in protein folding and recognition,” Biopolymers, vol. 80, no. 2-3, pp. 179–185, 2005.
[41]
B. W. Chellgren and T. P. Creamer, “Side-chain entropy effects on protein secondary structure formation,” Proteins, vol. 62, no. 2, pp. 411–420, 2006.
[42]
E. B. Unal, A. Gursoy, and B. Erman, “Conformational energies and entropies of peptides, and the peptide-protein binding problem,” Physical Biology, vol. 6, no. 3, Article ID 036014, 2009.
[43]
N. Eswar, C. Ramakrishnan, and N. Srinivasan, “Stranded in isolation: structural role of isolated extended strands in proteins,” Protein Engineering, vol. 16, no. 5, pp. 331–339, 2003.
[44]
Y. Mansiaux, A. P. Joseph, J.-C. Gelly, and A. G. de Brevern, “Assignment of polyproline ii conformation and analysis of sequence—structure relationship,” PLoS ONE, vol. 6, no. 3, Article ID e18401, 2011.
[45]
A. Zarrinpar, R. P. Bhattacharyya, and W. A. Lim, “The structure and function of proline recognition domains,” Science's STKE, vol. 2003, no. 179, p. RE8, 2003.
[46]
C. Freund, H. G. Schmalz, J. Sticht, and R. Kühne, “Proline-rich sequence recognition domain (PRD): ligands, function and inhibition,” in Protein–Protein Interactions as New Drug Targets, E. Klussmann and J. Scott, Eds., pp. 407–428, Springer, Berlin, Germany, 2008.
[47]
W. Gu and V. Helms, “Dynamical binding of proline-rich peptides to their recognition domains,” Biochimica et Biophysica Acta, vol. 1754, no. 1-2, pp. 232–238, 2005.
[48]
V. Neduva and R. B. Russell, “Proline-rich regions in transcriptional complexes: heading in many directions,” Science's STKE, vol. 2007, no. 369, article pe1, 2007.
[49]
B. R. Chandra, R. Gowthaman, R. R. Akhouri, D. Gupta, and A. Sharma, “Distribution of proline-rich (PxxP) motifs in distinct proteomes: functional and therapeutic implications for malaria and tuberculosis,” Protein Engineering, Design and Selection, vol. 17, no. 2, pp. 175–182, 2004.
[50]
R. Monta？ez, I. Navas-Delgado, M. A. Medina, J. F. Aldana-Montes, and F. Sánchez-Jiménez, “Information integration of protein-protein interactions as essential tools for immunomics,” Cellular Immunology, vol. 244, no. 2, pp. 84–86, 2006.
[51]
M. C. Díaz-Ramos, P. Engel, and R. Bastos, “Towards a comprehensive human cell-surface immunome database,” Immunology Letters, vol. 134, no. 2, pp. 183–187, 2011.
[52]
C. Ortutay and M. Vihinen, “Efficiency of the immunome protein interaction network increases during evolution,” Immunome Research, vol. 4, no. 1, article 4, 2008.
[53]
C. Ortutay and M. Vihinen, “Immunome Knowledge Base (IKB): an integrated service for immunome research,” BMC Immunology, vol. 10, article 3, 2009.
[54]
C. Freund, R. Kühne, H. Yang, S. Park, E. L. Reinherz, and G. Wagner, “Dynamic interaction of CD2 with the GYF and the SH3 domain of compartmentalized effector molecules,” EMBO Journal, vol. 21, no. 22, pp. 5985–5995, 2002.
[55]
A. V. Collins, D. W. Brodie, R. J. C. Gilbert et al., “The interaction properties of costimulatory molecules revisited,” Immunity, vol. 17, no. 2, pp. 201–210, 2002.
[56]
D. R. Fooksman, S. Vardhana, G. Vasiliver-Shamis et al., “Functional anatomy of T cell activation and synapse formation,” Annual Review of Immunology, vol. 28, pp. 79–105, 2010.
[57]
M. Gunzer, C. Weishaupt, A. Hillmer et al., “A spectrum of biophysical interaction modes between T cells and different antigen-presenting cells during priming in 3-D collagen and in vivo,” Blood, vol. 104, no. 9, pp. 2801–2809, 2004.
[58]
S. Hong, T. Chung, and D. Kim, “SH3 domain-peptide binding energy calculations based on structural ensemble and multiple peptide templates,” PLoS ONE, vol. 5, no. 9, Article ID e12654, pp. 1–8, 2010.
[59]
H. Zola, “Medical applications of leukocyte surface molecules—the CD molecules,” Molecular Medicine, vol. 12, no. 11-12, pp. 312–316, 2006.
[60]
M. Srinivasan and R. W. Roeske, “Immunomodulatory peptides from IgSF proteins: a review,” Current Protein and Peptide Science, vol. 6, no. 2, pp. 185–196, 2005.
[61]
J. P. C. Da Cunha, P. A. F. Galante, J. E. De Souza et al., “Bioinformatics construction of the human cell surfaceome,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 39, pp. 16752–16757, 2009.
[62]
P. Anton Van Der Merwe, “Modeling costimulation,” Nature Immunology, vol. 1, no. 3, pp. 194–195, 2000.
[63]
M. Srinivasan, I. E. Gienapp, S. S. Stuckman et al., “Suppression of experimental autoimmune encephalomyelitis using peptide mimics of CD28,” Journal of Immunology, vol. 169, no. 4, pp. 2180–2188, 2002.
[64]
M. Srinivasan, R. M. Wardrop, I. E. Gienapp, S. S. Stuckman, C. C. Whitacre, and P. T. P. Kaumaya, “A retro-inverso peptide mimic of CD28 encompassing the MYPPPY motif adopts a polyproline type II helix and inhibits encephalitogenic T cells in vitro,” Journal of Immunology, vol. 167, no. 1, pp. 578–585, 2001.
[65]
P. Loke and J. P. Allison, “Emerging mechanisms of immune regulation: the extended B7 family and regulatory T cells,” Arthritis Research and Therapy, vol. 6, no. 5, pp. 208–214, 2004.
[66]
P. A. Van Der Merwe and S. J. Davis, “Molecular interactions mediating T cell antigen recognition,” Annual Review of Immunology, vol. 21, pp. 659–684, 2003.
[67]
S. Wang, G. Zhu, K. Tamada, L. Chen, and J. Bajorath, “Ligand binding sites of inducible costimulator and high avidity mutants with improved function,” Journal of Experimental Medicine, vol. 195, no. 8, pp. 1033–1041, 2002.
[68]
C. C. Stamper, Y. Zhang, J. F. Tobin et al., “Crystal structure of the B7-1/CTLA-4 complex that inhibits human immune responses,” Nature, vol. 410, pp. 608–611, 2001.
[69]
M. Srinivasan, D. Lu, R. Eri, D. D. Brand, A. Haque, and J. S. Blum, “CD80 binding polyproline helical peptide inhibits T cell activation,” Journal of Biological Chemistry, vol. 280, no. 11, pp. 10149–10155, 2005.
[70]
R. Srinivasan and G. D. Rose, “A physical basis for protein secondary structure,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 25, pp. 14258–14263, 1999.
[71]
K. Chattopadhyay, S. Bhatia, A. Fiser, S. C. Almo, and S. G. Nathenson, “Structural basis of inducible costimulator ligand costimulatory function: determination of the cell surface oligomeric state and functional mapping of the receptor binding site of the protein,” Journal of Immunology, vol. 177, no. 6, pp. 3920–3929, 2006.
[72]
S. Ikemizu, R. J. C. Gilbert, J. A. Fennelly et al., “Structure and dimerization of a soluble form of B7-1,” Immunity, vol. 12, no. 1, pp. 51–60, 2000.
[73]
X. Zhang, J. C. D. Schwartz, S. C. Almo, and S. G. Nathenson, “Crystal structure of the receptor-binding domain of human B7-2: insights into organization and signaling,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 5, pp. 2586–2591, 2003.
[74]
S. Dudhgaonkar, A. Thyagarajan, and D. Sliva, “Suppression of the inflammatory response by triterpenes isolated from the mushroom Ganoderma lucidum,” International Immunopharmacology, vol. 9, no. 11, pp. 1272–1280, 2009.
[75]
R. Eri, K. N. Kodumudi, D. J. Summerlin, and M. Srinivasan, “Suppression of colon inflammation by CD80 blockade: evaluation in two murine models of inflammatory bowel disease,” Inflammatory Bowel Diseases, vol. 14, no. 4, pp. 458–470, 2008.
[76]
M. Srinivasan, R. Eri, S. L. Zunt, D. J. Summerlin, D. D. Brand, and J. S. Blum, “Suppression of immune responses in collagen-induced arthritis by a rationally designed CD80-binding peptide agent,” Arthritis and Rheumatism, vol. 56, no. 2, pp. 498–508, 2007.
[77]
M. Radulovic and J. Godovac-Zimmermann, “Proteomic approaches to understanding the role of the cytoskeleton in host-defense mechanisms,” Expert Review of Proteomics, vol. 8, no. 1, pp. 117–126, 2011.
[78]
A. Disanza, A. Steffen, M. Hertzog, E. Frittoli, K. Rottner, and G. Scita, “Actin polymerization machinery: the finish line of signaling networks, the starting point of cellular movement,” Cellular and Molecular Life Sciences, vol. 62, no. 9, pp. 955–970, 2005.
[79]
D. C. Wickramarachchi, A. N. Theofilopoulos, and D. H. Kono, “Immune pathology associated with altered actin cytoskeleton regulation,” Autoimmunity, vol. 43, no. 1, pp. 64–75, 2010.
[80]
M. P. Blundell, A. Worth, G. Bouma, and A. J. Thrasher, “The Wiskott-Aldrich syndrome: the actin cytoskeleton and immune cell function,” Disease Markers, vol. 29, no. 3-4, pp. 157–175, 2010.
[81]
Y. Sasahara, R. Rachid, M. J. Byrne et al., “Mechanism of recruitment of WASP to the immunological synapse and of its activation following TCR ligation,” Molecular Cell, vol. 10, no. 6, pp. 1269–1281, 2002.
[82]
A. J. Thrasher and S. O. Burns, “WASP: a key immunological multitasker,” Nature Reviews Immunology, vol. 10, no. 3, pp. 182–192, 2010.
[83]
F. C. Peterson, Q. Deng, M. Zettl et al., “Multiple WASP-interacting protein recognition motifs are required for a functional interaction with N-WASP,” Journal of Biological Chemistry, vol. 282, no. 11, pp. 8446–8453, 2007.
[84]
N. Ramesh, I. M. Antón, J. H. Hartwig, and R. S. Geha, “WIP, a protein associated with Wiskott-Aldrich syndrome protein, induces actin polymerization and redistribution in lymphoid cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 26, pp. 14671–14676, 1997.
[85]
S. L. Bras, M. Massaad, S. Koduru et al., “WIP is critical for T cell responsiveness to IL-2,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 18, pp. 7519–7524, 2009.
[86]
N. Ramesh and R. Geha, “Recent advances in the biology of WASP and WIP,” Immunologic Research, vol. 44, no. 1–3, pp. 99–111, 2009.
[87]
J. L. Cannon, C. M. Labno, G. Bosco et al., “WASP recruitment to the T cell: APC contact site occurs independently of Cdc42 activation,” Immunity, vol. 15, no. 2, pp. 249–259, 2001.
[88]
X. Dong, G. Patino-Lopez, F. Candotti, and S. Shaw, “Structure-function analysis of the WIP role in T cell receptor-stimulated NFAT activation: evidence that WIP-WASP dissociation is not required and that the WIP NH2 terminus is inhibitory,” Journal of Biological Chemistry, vol. 282, no. 41, pp. 30303–30310, 2007.
[89]
C. Combet, M. Jambon, G. Deléage, and C. Geourjon, “Geno3D: automatic comparative molecular modelling of protein,” Bioinformatics, vol. 18, no. 1, pp. 213–214, 2002.
[90]
F. Kiefer, K. Arnold, M. Künzli, L. Bordoli, and T. Schwede, “The SWISS-MODEL repository and associated resources,” Nucleic Acids Research, vol. 37, no. 1, pp. D387–D392, 2009.
[91]
N. Petrovsky, “Immunome research—five years on,” Immunome Research, vol. 7, no. 1, pp. 1–4, 2011.
[92]
B. F. Volkman, K. E. Prehoda, J. A. Scott, F. C. Peterson, and W. A. Lim, “Structure of the N-WASP EVH1 domain-WIP complex: insight into the molecular basis of Wiskott-Aldrich Syndrome,” Cell, vol. 111, no. 4, pp. 565–576, 2002.
[93]
M. J. Massaad, N. Ramesh, S. Le Bras et al., “A peptide derived from the Wiskott-Aldrich syndrome (WAS) protein-interacting protein (WIP) restores WAS protein level and actin cytoskeleton reorganization in lymphocytes from patients with WAS mutations that disrupt WIP binding,” Journal of Allergy and Clinical Immunology, vol. 127, no. 4, pp. 998–1005.e2, 2011.
[94]
R. Tjian and T. Maniatis, “Transcriptional activation: a complex puzzle with few easy pieces,” Cell, vol. 77, no. 1, pp. 5–8, 1994.
[95]
S. Triezenberg, “Structure and function of transcriptional activation domains,” Current Opinion in Genetics and Development, vol. 5, no. 2, pp. 190–196, 1995.
[96]
H. P. Gerber, K. Seipel, O. Georgiev et al., “Transcriptional activation modulated by homopolymeric glutamine and proline stretches,” Science, vol. 263, no. 5148, pp. 808–811, 1994.
[97]
H. M. Chan and N. B. La Thangue, “p300/CBP proteins: HATs for transcriptional bridges and scaffolds,” Journal of Cell Science, vol. 114, no. 13, pp. 2363–2373, 2001.
[98]
D. Dornan, H. Shimizu, L. Burch, A. J. Smith, and T. R. Hupp, “The proline repeat domain of p53 binds directly to the transcriptional coactivator p300 and allosterically controls DNA-dependent acetylation of p53,” Molecular and Cellular Biology, vol. 23, no. 23, pp. 8846–8861, 2003.
[99]
A. C. Joerger and A. R. Fersht, “Structural biology of the tumor suppressor p53,” Annual Review of Biochemistry, vol. 77, pp. 557–582, 2008.
[100]
A. C. Joerger and A. R. Fersht, “The tumor suppressor p53: from structures to drug discovery,” Cold Spring Harbor Perspectives in Biology, vol. 2, no. 6, p. a000919, 2010.
[101]
N. Dumaz, D. M. Milne, L. J. Jardine, and D. W. Meek, “Critical roles for the serine 20, but not the serine 15, phosphorylation site and for the polyproline domain in regulating p53 turnover,” Biochemical Journal, vol. 359, no. 2, pp. 459–464, 2001.
[102]
P. A. Baeuerle and T. Henkel, “Function and activation of NF-κB in the immune system,” Annual Review of Immunology, vol. 12, pp. 141–179, 1994.
[103]
M. E. Gerritsen, A. J. Williams, A. S. Neish, S. Moore, Y. Shi, and T. Collins, “CREB-binding protein/p300 are transcriptional coactivators of p65,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 7, pp. 2927–2932, 1997.
[104]
M. A. Calzado, S. Bacher, and M. L. Schmitz, “NF-κB inhibitors for the treatment of inflammatory diseases and cancer,” Current Medicinal Chemistry, vol. 14, no. 3, pp. 367–376, 2007.
[105]
L. I. McKay and J. A. Cidlowski, “CBP (CREB binding protein) integrates NF-κB (nuclear factor-κB) and glucocorticoid receptor physical interactions and antagonism,” Molecular Endocrinology, vol. 14, no. 8, pp. 1222–1234, 2000.
[106]
N. C. Nicolaides, Z. Galata, T. Kino, G. P. Chrousos, and E. Charmandari, “The human glucocorticoid receptor: molecular basis of biologic function,” Steroids, vol. 75, no. 1, pp. 1–12, 2010.
[107]
F. D'Adamio, O. Zollo, R. Moraca et al., “A new dexamethasone-induced gene of the leucine zipper family protects T lymphocytes from TCR/CD3-activated cell death,” Immunity, vol. 7, no. 6, pp. 803–812, 1997.
[108]
E. Ayroldi, O. Zollo, A. Bastianelli et al., “GILZ mediates the antiproliferative activity of glucocorticoids by negative regulation of Ras signaling,” Journal of Clinical Investigation, vol. 117, no. 6, pp. 1605–1615, 2007.
[109]
E. Ayroldi and C. Riccardi, “Glucocorticoid-induced leucine zipper (GILZ): a new important mediator of glucocorticoid action,” FASEB Journal, vol. 23, no. 11, pp. 3649–3658, 2009.
[110]
C. Riccardi, “GILZ (glucocorticoid-induced leucine zipper), a mediator of the anti-inflammatory and immunosuppressive activity of glucocorticoids,” Annali di Igiene, vol. 22, no. 1, supplement 1, pp. 53–59, 2010.
[111]
L. Cannarile, S. Cuzzocrea, L. Santucci et al., “Glucocorticoid-induced leucine zipper is protective in Th1-mediated models of colitis,” Gastroenterology, vol. 136, no. 2, pp. 530–541, 2009.
[112]
E. Ayroldi, G. Migliorati, S. Bruscoli et al., “Modulation of T-cell activation by the glucocorticoid-induced leucine zipper factor via inhibition of nuclear factor κB,” Blood, vol. 98, no. 3, pp. 743–753, 2001.
[113]
B. Di Marco, M. Massetti, S. Bruscoli et al., “Glucocorticoid-induced leucine zipper (GILZ)/NF-κB interaction: role of GILZ homo-dimerization and C-terminal domain,” Nucleic Acids Research, vol. 35, no. 2, pp. 517–528, 2007.
[114]
R. Bhattacharyya and P. Chakrabarti, “Stereospecific interactions of proline residues in protein structures and complexes,” Journal of Molecular Biology, vol. 331, no. 4, pp. 925–940, 2003.
[115]
M. L. Schmitz, M. A. Dos Santos Silva, H. Altmann, M. Czisch, T. A. Holak, and P. A. Baeuerle, “Structural and functional analysis of the NF-κB p65 C terminus. An acidic and modular transactivation domain with the potential to adopt an α-helical conformation,” Journal of Biological Chemistry, vol. 269, no. 41, pp. 25613–25620, 1994.
[116]
A. K. Dunker, J. D. Lawson, C. J. Brown et al., “Intrinsically disordered protein,” Journal of Molecular Graphics and Modelling, vol. 19, no. 1, pp. 26–59, 2001.
[117]
M. Srinivasan and S. Janardhanam, “Novel p65 binding glucocorticoid-induced leucine zipper peptide suppresses experimental autoimmune encephalomyelitis,” Journal of Biological Chemistry, vol. 286, no. 52, pp. 44799–44810, 2011.
[118]
J. Oberoi, M. W. Richards, S. Crumpler, N. Brown, J. Blagg, and R. Bayliss, “Structural basis of poly(ADP-ribose) recognition by the multizinc binding domain of Checkpoint with Forkhead-associated and RING domains (CHFR),” Journal of Biological Chemistry, vol. 285, no. 50, pp. 39348–39358, 2010.
[119]
M. L. Privalsky, “The role of corepressors in transcriptional regulation by nuclear hormone receptors,” Annual Review of Physiology, vol. 66, pp. 315–360, 2004.
[120]
K. De Bosscher, W. Vanden Berghe, and G. Haegeman, “Cross-talk between nuclear receptors and nuclear factor κB,” Oncogene, vol. 25, no. 51, pp. 6868–6886, 2006.
[121]
J. Li, J. Wang, J. Wang et al., “Both corepressor proteins SMRT and N-CoR exist in large protein complexes containing HDAC3,” EMBO Journal, vol. 19, no. 16, pp. 4342–4350, 2000.
[122]
J. E. Hoberg, A. E. Popko, C. S. Ramsey, and M. W. Mayo, “IκB kinase α-mediated derepression of SMRT potentiates acetylation of RelA/p65 by p300,” Molecular and Cellular Biology, vol. 26, no. 2, pp. 457–471, 2006.
[123]
S. K. Lee, J. H. Kim, Y. C. Lee, J. Cheong, and J. W. Lee, “Silencing mediator of retinoic acid and thyroid hormone receptors, as a novel transcriptional corepressor molecule of activating protein-1, nuclear factor-κB, and serum response factor,” Journal of Biological Chemistry, vol. 275, no. 17, pp. 12470–12474, 2000.
[124]
S. Ansieau and A. Leutz, “The conserved Mynd domain of BS69 binds cellular and oncoviral proteins through a common PXLXP motif,” Journal of Biological Chemistry, vol. 277, no. 7, pp. 4906–4910, 2002.
[125]
P. D. Gottlieb, S. A. Pierce, R. J. Sims et al., “Bop encodes a muscle-restricted protein containing MYND and SET domains and is essential for cardiac differentiation and morphogenesis,” Nature Genetics, vol. 31, no. 1, pp. 25–32, 2002.
[126]
J. Lausen, S. Cho, S. Liu, and M. H. Werner, “The nuclear receptor co-repressor (N-CoR) utilizes repression domains I and III for interaction and co-repression with ETO,” Journal of Biological Chemistry, vol. 279, no. 47, pp. 49281–49288, 2004.
[127]
J. M. Matthews, M. Bhati, E. Lehtomaki, R. E. Mansfield, L. Cubeddu, and J. P. Mackay, “It takes two to tango: the structure and function of LIM, RING, PHD and MYND domains,” Current Pharmaceutical Design, vol. 15, no. 31, pp. 3681–3696, 2009.
[128]
H. P. Liu, P. J. Chung, C. L. Liang, and Y. S. Chang, “The MYND domain-containing protein BRAM1 inhibits lymphotoxin beta receptor-mediated signaling through affecting receptor oligomerization,” Cellular Signalling, vol. 23, no. 1, pp. 80–88, 2011.
[129]
B. A. Hug and M. A. Lazar, “ETO interacting proteins,” Oncogene, vol. 23, no. 24, pp. 4270–4274, 2004.
[130]
Y. Liu, W. Chen, J. Gaudet et al., “Structural basis for recognition of SMRT/N-CoR by the MYND domain and its contribution to AML1/ETO's activity,” Cancer Cell, vol. 11, no. 6, pp. 483–497, 2007.
[131]
M. Yan, S. A. Burel, L. F. Peterson et al., “Deletion of an AML1-ETO C-terminal NcoR/SMRT-interacting region strongly induces leukemia development,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 49, pp. 17186–17191, 2004.
[132]
A. K. Dunker and V. N. Uversky, “Drugs for 'protein clouds': targeting intrinsically disordered transcription factors,” Current Opinion in Pharmacology, vol. 10, no. 6, pp. 782–788, 2010.
[133]
L. L. Conte, C. Chothia, and J. Janin, “The atomic structure of protein-protein recognition sites,” Journal of Molecular Biology, vol. 285, no. 5, pp. 2177–2198, 1999.
[134]
B. Groner, “Peptides as drugs, discovery and development,” in Peptides as Drugs, Discovery and Development, B. Groner, Ed., pp. 1–8, Wiley-VCH, Weinheim, Germany, 2009.
