Using peptides to study protein-protein interactions.

Protein-protein interactions (PPIs) govern all aspects of cell function and, as such, are a major target for research and therapeutic intervention. A major rate-limiting step in PPI research is the expression and purification of full-length proteins. The use of peptides to study PPIs significantly facilitates the structural and biophysical characterization of PPIs as well as the effort to develop drugs to control PPIs. Here we describe examples for the use of peptides to study PPI and some of the important experimental methods that are used in the field. Peptides have proved to be excellent tools to study PPIs and have been contributing both for understanding mechanisms of PPIs as well as for drug design for PPI modulation.

[1]  S. Fields,et al.  A novel genetic system to detect protein–protein interactions , 1989, Nature.

[2]  Georgios A. Dalkas,et al.  Insights into the anthrax lethal factor–substrate interaction and selectivity using docking and molecular dynamics simulations , 2009, Protein science : a publication of the Protein Society.

[3]  S. Kent,et al.  Convergent chemical synthesis and crystal structure of a 203 amino acid "covalent dimer" HIV-1 protease enzyme molecule. , 2007, Angewandte Chemie.

[4]  Michelle R. Arkin,et al.  Small-molecule inhibitors of protein–protein interactions: progressing towards the dream , 2004, Nature Reviews Drug Discovery.

[5]  J. Briggs,et al.  Computational insights into the interaction of the anthrax lethal factor with the N‐terminal region of its substrates , 2009, Proteins.

[6]  A. Fersht,et al.  Binding of Rad51 and Other Peptide Sequences to a Promiscuous, Highly Electrostatic Binding Site in p53* , 2005, Journal of Biological Chemistry.

[7]  A. Friedler,et al.  Peptides derived from HIV‐1 Rev inhibit HIV‐1 integrase in a shiftide mechanism , 2008, Biopolymers.

[8]  N. Neamati,et al.  Inhibition of HIV-1 integrase activity by synthetic peptides derived from the HIV-1 HXB2 Pol region of the viral genome. , 2006, Bioorganic & medicinal chemistry letters.

[9]  Zhimin Xiang,et al.  Backbone cyclic peptidomimetic melanocortin-4 receptor agonist as a novel orally administrated drug lead for treating obesity. , 2008, Journal of medicinal chemistry.

[10]  R. Aebersold,et al.  Mass spectrometry-based proteomics , 2003, Nature.

[11]  P. Dawson,et al.  Synthesis of native proteins by chemical ligation. , 2000, Annual review of biochemistry.

[12]  Kai Hilpert,et al.  Peptide arrays on cellulose support: SPOT synthesis, a time and cost efficient method for synthesis of large numbers of peptides in a parallel and addressable fashion , 2007, Nature Protocols.

[13]  A. Fersht,et al.  Binding of p53-derived ligands to MDM2 induces a variety of long range conformational changes. , 2004, Journal of molecular biology.

[14]  J. Scheller,et al.  Synthetic Mimetics of the gp130 Binding Site for Viral Interleukin‐6 as Inhibitors of the vIL‐6–gp130 Interaction , 2008, Chemical biology & drug design.

[15]  Shubhra Ghosh Dastidar,et al.  Rational design and biophysical characterization of thioredoxin-based aptamers: insights into peptide grafting. , 2010, Journal of molecular biology.

[16]  Sheng Jiang,et al.  Design, synthesis, and characterization of a potent, nonpeptide, cell-permeable, bivalent Smac mimetic that concurrently targets both the BIR2 and BIR3 domains in XIAP. , 2007, Journal of the American Chemical Society.

[17]  A. Schepartz,et al.  Paralog-selective ligands for bcl-2 proteins. , 2005, Journal of the American Chemical Society.

[18]  H. Kessler,et al.  N‐Methylation of Peptides: A New Perspective in Medicinal Chemistry , 2009 .

[19]  J. Schneider-Mergener,et al.  Substrate Specificity of the SecB Chaperone* , 1999, The Journal of Biological Chemistry.

[20]  David C. Fry.  Drug‐Like Inhibitors of Protein—Protein Interactions: A Structural Examination of Effective Protein Mimicry , 2009 .

[21]  A. Strosberg,et al.  Peptide inhibitors of hepatitis C virus core oligomerization and virus production. , 2009, The Journal of general virology.

[22]  A. Friedler,et al.  Inhibition of nuclear import by backbone cyclic peptidomimetics derived from the HIV-1 MA NLS sequence. , 2002, Biochimica et biophysica acta.

[23]  V. Hruby,et al.  Peptidomimetics, a synthetic tool of drug discovery. , 2008, Current opinion in chemical biology.

[24]  B. Séraphin,et al.  A generic protein purification method for protein complex characterization and proteome exploration , 1999, Nature Biotechnology.

[25]  A. Toporik,et al.  A Novel Peptide Agonist of Formyl-Peptide Receptor-Like 1 (ALX) Displays Anti-Inflammatory and Cardioprotective Effects , 2009, Journal of Pharmacology and Experimental Therapeutics.

[26]  Raymond E. Moellering,et al.  Direct inhibition of the NOTCH transcription factor complex , 2009, Nature.

[27]  A. Friedler,et al.  Correlation between shiftide activity and HIV-1 integrase inhibition by a peptide selected from a combinatorial library. , 2008, Journal of molecular biology.

[28]  Kuan Wang,et al.  Titin as a Giant Scaffold for Integrating Stress and Src Homology Domain 3-mediated Signaling Pathways , 2006, Journal of Biological Chemistry.

[29]  Ernst Schönbrunn,et al.  Structure-based Design of High Affinity Peptides Inhibiting the Interaction of p53 with MDM2 and MDMX* , 2009, The Journal of Biological Chemistry.

[30]  C. Turck,et al.  Evidence for α-Helical Conformation of an Essential N-terminal Region in the Human Bcl2 Protein* , 1996, The Journal of Biological Chemistry.

[31]  Erinna F. Lee,et al.  Crystal structure of ABT-737 complexed with Bcl-xL: implications for selectivity of antagonists of the Bcl-2 family , 2007, Cell Death and Differentiation.

[32]  Andrew D. Hamilton,et al.  Terphenyl-Based Bak BH3 α-Helical Proteomimetics as Low-Molecular-Weight Antagonists of Bcl-xL , 2005 .

[33]  S. Kent.  Total chemical synthesis of proteins. , 2009, Chemical Society reviews.

[34]  D. Craik.  Circling the enemy: cyclic proteins in plant defence. , 2009, Trends in plant science.

[35]  Giovanna Zinzalla,et al.  Targeting protein-protein interactions for therapeutic intervention: a challenge for the future. , 2009, Future medicinal chemistry.

[36]  Marina Cretich,et al.  Protein and peptide arrays: recent trends and new directions. , 2006, Biomolecular engineering.

[37]  E. Jaffe.  Morpheeins--a new structural paradigm for allosteric regulation. , 2005, Trends in biochemical sciences.

[38]  G. Verdine,et al.  An All-Hydrocarbon Cross-Linking System for Enhancing the Helicity and Metabolic Stability of Peptides , 2000 .

[39]  Linkage between fructose 1,6-bisphosphate binding and the dimer-tetramer equilibrium of Escherichia coli glycerol kinase: critical behavior arising from change of ligand stoichiometry. , 2003, Biochemistry.

[40]  S. Fesik,et al.  forms an inactivating dimer with Bcl-XL . Bad is a BH 3 domain-containing protein , 1997 .

[41]  R. Hodges,et al.  Biophysical characterization of HRC peptide analogs interaction with heptad repeat regions of the SARS-coronavirus Spike fusion protein core , 2006, Journal of Structural Biology.

[42]  A. Wand,et al.  Arylamide derivatives as peptidomimetic inhibitors of calmodulin. , 2006, Organic letters.

[43]  M. Vidal,et al.  Interactome: gateway into systems biology. , 2005, Human molecular genetics.

[44]  Joshua A. Kritzer,et al.  Miniature Protein Inhibitors of the p53–hDM2 Interaction , 2006, Chembiochem : a European journal of chemical biology.

[45]  David J. Craik,et al.  Seamless Proteins Tie Up Their Loose Ends , 2006, Science.

[46]  A. E. Hirsh,et al.  Coevolution of gene expression among interacting proteins , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[47]  S. Rüdiger,et al.  Binding specificity of an alpha-helical protein sequence to a full-length Hsp70 chaperone and its minimal substrate-binding domain. , 2006, Biochemistry.

[48]  R. Hoffmann,et al.  Development of a pharmacologically improved peptide agonist of the leptin receptor. , 2008, Biochimica et biophysica acta.

[49]  S. Gellman,et al.  Targeting protein-protein interactions: lessons from p53/MDM2. , 2007, Biopolymers.

[50]  A. Fersht,et al.  A peptide that binds and stabilizes p53 core domain: Chaperone strategy for rescue of oncogenic mutants , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[51]  J. Adamson,et al.  Design and Chemical Synthesis of a Homogeneous Polymer-Modified Erythropoiesis Protein , 2003, Science.

[52]  P. Arora,et al.  Atomic structure of a short alpha-helix stabilized by a main chain hydrogen-bond surrogate. , 2008, Journal of the American Chemical Society.

[53]  S. Rüdiger,et al.  Interaction of Hsp70 chaperones with substrates , 1997, Nature Structural Biology.

[54]  J. Schneider-Mergener,et al.  Binding specificity of Escherichia coli trigger factor , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[55]  H. Benyamini,et al.  Molecular basis of the interaction between the antiapoptotic Bcl-2 family proteins and the proapoptotic protein ASPP2 , 2008, Proceedings of the National Academy of Sciences.

[56]  H. Benyamini,et al.  The Structure and Interactions of the Proline-rich Domain of ASPP2* , 2008, Journal of Biological Chemistry.

[57]  C. Gilon,et al.  Structure-activity relationship and metabolic stability studies of backbone cyclization and N-methylation of melanocortin peptides. , 2008, Biopolymers.

[58]  Joseph Rosenbluh,et al.  Inhibiting HIV-1 integrase by shifting its oligomerization equilibrium , 2007, Proceedings of the National Academy of Sciences.

[59]  Christopher L. McClendon,et al.  Reaching for high-hanging fruit in drug discovery at protein–protein interfaces , 2007, Nature.

[60]  Hui Lu,et al.  Correlation between gene expression profiles and protein-protein interactions within and across genomes , 2005, Bioinform..

[61]  D. Craik,et al.  Discovery, structure and biological activities of cyclotides. , 2004, Advanced drug delivery reviews.

[62]  Bernd Bukau,et al.  Substrate specificity of the DnaK chaperone determined by screening cellulose‐bound peptide libraries , 1997, The EMBO journal.

[63]  G. Byk,et al.  Backbone cyclization: A new method for conferring conformational constraint on peptides , 1991, Biopolymers.

[64]  A. Fersht,et al.  Two sequence motifs from HIF-1α bind to the DNA-binding site of p53 , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[65]  R. B. Merrifield.  Solid phase peptide synthesis. I. the synthesis of a tetrapeptide , 1963 .

[66]  R. Meadows,et al.  Structure of Bcl-xL-Bak Peptide Complex: Recognition Between Regulators of Apoptosis , 1997, Science.

[67]  J. Eichler.  Peptides as protein binding site mimetics. , 2008, Current opinion in chemical biology.

[68]  A. Fersht,et al.  Molecular mechanism of the interaction between MDM2 and p53. , 2002, Journal of molecular biology.

[69]  Natasa Przulj,et al.  High-Throughput Mapping of a Dynamic Signaling Network in Mammalian Cells , 2005, Science.

[70]  E. Pérez-Payá,et al.  Membrane promotes tBID interaction with BCL(XL). , 2009, Nature structural & molecular biology.

[71]  A. Friedler,et al.  Development of a Functional Backbone Cyclic Mimetic of the HIV-1 Tat Arginine-rich Motif* , 2000, The Journal of Biological Chemistry.

[72]  H. Benyamini,et al.  A model for the interaction between NF‐kappa‐B and ASPP2 suggests an I‐kappa‐B‐like binding mechanism , 2009, Proteins.

[73]  M. Vidal.  A unifying view of 21st century systems biology , 2009, FEBS letters.

[74]  R. Frank.  Spot-synthesis: an easy technique for the positionally addressable, parallel chemical synthesis on a membrane support , 1992 .

[75]  Lei Tang,et al.  Shape shifting leads to small-molecule allosteric drug discovery. , 2008, Chemistry & biology.

[76]  A. Friedler,et al.  Peptide inhibitors of HIV-1 integrase: from mechanistic studies to improved lead compounds. , 2009, Bioorganic & medicinal chemistry.

[77]  Thomas Kolter,et al.  Chemical Chaperones — A New Concept in Drug Research , 2003 .

[78]  Alexander Wlodawer,et al.  Control of tetrapyrrole biosynthesis by alternate quaternary forms of porphobilinogen synthase , 2003, Nature Structural Biology.

[79]  Astrid A. Ortiz,et al.  A Novel Long-Acting Selective Neuropeptide Y2 Receptor Polyethylene Glycol-Conjugated Peptide Agonist Reduces Food Intake and Body Weight and Improves Glucose Metabolism in Rodents , 2007, Journal of Pharmacology and Experimental Therapeutics.

[80]  A. Friedler,et al.  The Positively Charged Region of the Myosin IIC Non-helical Tailpiece Promotes Filament Assembly* , 2009, The Journal of Biological Chemistry.

[81]  S. Korsmeyer,et al.  Activation of Apoptosis in Vivo by a Hydrocarbon-Stapled BH3 Helix , 2004, Science.

[82]  Chong Li,et al.  Structural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX , 2009, Proceedings of the National Academy of Sciences.

[83]  S. Fesik,et al.  Bad is a BH3 domain-containing protein that forms an inactivating dimer with Bcl-XL , 1997, Molecular and cellular biology.

[84]  A. Friedler,et al.  Backbone cyclic peptide, which mimics the nuclear localization signal of human immunodeficiency virus type 1 matrix protein, inhibits nuclear import and virus production in nondividing cells. , 1998, Biochemistry.

[85]  Haim Ashkenazy,et al.  Peptides modulating conformational changes in secreted chaperones: From in silico design to preclinical proof of concept , 2009, Proceedings of the National Academy of Sciences.

[86]  J. Stewart.  Solid Phase Peptide Synthesis , 1984 .

[87]  A. Fersht,et al.  Four domains of p300 each bind tightly to a sequence spanning both transactivation subdomains of p53 , 2007, Proceedings of the National Academy of Sciences.

[88]  A. Mittermaier,et al.  Binding mechanism of an SH3 domain studied by NMR and ITC. , 2009, Journal of the American Chemical Society.

[89]  P. Wolynes,et al.  Induced fit, folding, and recognition of the NF-kappaB-nuclear localization signals by IkappaBalpha and IkappaBbeta. , 2007, Journal of molecular biology.

[90]  A. Fersht,et al.  Structural distortion of p53 by the mutation R249S and its rescue by a designed peptide: implications for "mutant conformation". , 2004, Journal of molecular biology.

[91]  D. Craik.  Chemistry. Seamless proteins tie up their loose ends. , 2006, Science.

[92]  G. Byk,et al.  Comparison of the conformation of active and nonactive backbone cyclic analogs of substance P as a tool to elucidate features of the bioactive conformation: NMR and molecular dynamics in DMSO and water. , 1994, Journal of medicinal chemistry.

[93]  I. Haro,et al.  Synthetic peptides of hepatitis G virus (GBV-C/HGV) in the selection of putative peptide inhibitors of the HIV-1 fusion peptide. , 2009, The journal of physical chemistry. B.

[94]  G. Bitan,et al.  Synthesis and biological activity of NK-1 selective, N-backbone cyclic analogs of the C-terminal hexapeptide of substance P. , 1996, Journal of medicinal chemistry.

[95]  J. Chin,et al.  Concerted evolution of structure and function in a miniature protein. , 2001, Journal of the American Chemical Society.

[96]  J. Chin,et al.  Design and Evolution of a Miniature Bcl-2 Binding Protein. , 2001, Angewandte Chemie.

[97]  Gerhard Hummer,et al.  How mitogen-activated protein kinases recognize and phosphorylate their targets: A QM/MM study. , 2009, Journal of the American Chemical Society.

[98]  J. Chin,et al.  Methodology for optimizing functional miniature proteins based on avian pancreatic polypeptide using phage display. , 2001, Bioorganic & medicinal chemistry letters.