Knitting and untying the protein network: Modulation of protein ensembles as a therapeutic strategy

doi:10.1002/pro.43

Review

You have full text access to this OnlineOpen article

Knitting and untying the protein network: Modulation of protein ensembles as a therapeutic strategy

Susana Gordo¹,
Ernest Giralt^1,2,*

Article first published online: 29 DEC 2008

DOI: 10.1002/pro.43

Issue

Protein Science

Volume 18, Issue 3, pages 481–493, March 2009

Additional Information

How to Cite

Gordo, S. and Giralt, E. (2009), Knitting and untying the protein network: Modulation of protein ensembles as a therapeutic strategy. Protein Science, 18: 481–493. doi: 10.1002/pro.43

Author Information

¹
Institute for Research in Biomedicine, Parc Científic de Barcelona, Baldiri i Reixac 10, 08028 Barcelona, Spain
²
Department of Organic Chemistry, Universitat de Barcelona, Martí i Franqués 1, 08028 Barcelona, Spain

Email: Ernest Giralt (ernest.giralt@irbbarcelona.org)

^*Institute for Research in Biomedicine, Parc Científic de Barcelona, Baldiri i Reixac 10, 08028 Barcelona, Spain

Publication History

Issue published online: 23 FEB 2009
Article first published online: 29 DEC 2008
Accepted manuscript online: 29 DEC 2008 12:00AM EST
Manuscript Accepted: 24 NOV 2008
Manuscript Revised: 16 OCT 2008
Manuscript Received: 11 JUL 2008

Funded by

Plan Nacional del Ministerio de Educación y Ciencia. Grant Number: BIO2008-0799
Generalitat de Catalunya—Xarxa de Referencia en Biotechnologia

ARTICLE TOOLS

View Full Article (HTML) Get PDF (438K)

References

1
Cusick ME, Klitgord N, Vidal M, Hill DE ( 2005) Interactome: gateway into systems biology. Hum Mol Genet 14: R171–R181.
2
Jeong H, Mason SP, Barabási A-L, Oltvai ZN ( 2001) Lethality and centrality in protein networks. Nature 411: 41–42.
3
He X, Zhang J ( 2006) Why do hubs tend to be essential in protein networks? PLoS Genet 2: e88.
4
Wright PE, Dyson HJ ( 1999) Intrinsically unstructured proteins: re-assessing the protein structure-function paradigm. J Mol Biol 293: 321–331.
5
Uversky VN ( 2002) Natively unfolded proteins: a point where biology waits for physics. Protein Sci 11: 739–756.
Direct Link:
6
Dyson HJ, Wright PE ( 2005) Intrinsically unstructured proteins and their functions. Nat Rev Mol Cell Biol 6: 197–208.
7
Dunker AK, Cortese MS, Romero P, Iakoucheva LM, Uversky VN ( 2005) Flexible nets. The roles of intrinsic disorder in protein interaction networks. FEBS J 272: 5129–5148.
Direct Link:
8
Patil A, Nakamura H ( 2006) Disordered domains and high surface charge confer hubs with the ability to interact with multiple proteins in interaction networks. FEBS Lett 580: 2041–2045.
9
Sali A, Glaeser R, Earnest T, Baumeister W ( 2003) From words to literature in structural proteomics. Nature 422: 216–225.
10
Goodsell DS, Olson AJ ( 2000) Structural symmetry and protein function. Annu Rev Biophys Biomol Struct 29: 105–153.
11
Goodsell DS ( 1991) Inside a living cell. Trends Biochem Sci 16: 203–206.
12
Keskin O, Gursoy A, Ma B, Nussinov R ( 2008) Principles of protein–protein interactions: what are the preferred ways for proteins to interact? Chem Rev 108: 1225–1244.
13
Nooren IM, Thornton JM ( 2003a) Diversity of protein–protein interactions. EMBO J 22: 3486–3492.
14
Nooren IM, Thornton JM ( 2003b) Structural characterisation and functional significance of transient protein–protein interactions. J Mol Biol 325: 991–1018.
15
Ofran Y, Rost B ( 2003) Analysing six types of protein–protein interfaces. J Mol Biol 325: 377–387.
16
Lo Conte L, Chothia C, Janin J ( 1999) The atomic structure of protein–protein recognition sites. J Mol Biol 285: 2177–2198.
- CrossRef,
- PubMed,
- CAS
17
De S, Krishnadev O, Srinivasan N, Rekha N ( 2005) Interaction preferences across protein–protein interfaces of obligatory and non-obligatory components are different. BMC Struct Biol 5: 15.
18
Glaser F, Steinberg DM, Vakser IA, Ben-Tal N ( 2001) Residue frequencies and pairing preferences at protein-protein interfaces. Proteins 43: 89–102.
Direct Link:
19
Keskin O, Ma B, Nussinov R ( 2005) Hot regions in protein–protein interactions: the organization and contribution of structurally conserved hot spot residues. J Mol Biol 345: 1281–1294.
20
Hubbard SJ, Argos P ( 1994) Cavities and packing at protein interfaces. Protein Sci 3: 2194–2206.
Direct Link:
21
Raschke TM ( 2006) Water structure and interactions with protein surfaces. Curr Opin Struct Biol 16: 152–159.
22
Reichmann D, Rahat O, Cohen M, Neuvirth H, Schreiber G ( 2007) The molecular architecture of protein–protein binding sites. Curr Opin Struct Biol 17: 67–76.
23
Teyra J, Pisabarro MT ( 2007) Characterization of interfacial solvent in protein complexes and contribution of wet spots to the interface description. Proteins 67: 1087–1095.
Direct Link:
24
Stites WE ( 1997) Protein–protein interactions: interface structure, binding thermodynamics, and mutational analysis. Chem Rev 97: 1233–1250.
25
Cohen M, Reichmann D, Neuvirth H, Schreiber G ( 2008) Similar chemistry, but different bond preferences in inter versus intra-protein interactions. Proteins 72: 741–753.
Direct Link:
26
Hu Z, Ma B, Wolfson H, Nussinov R ( 2000) Conservation of polar residues as hot spots at protein interfaces. Proteins 39: 331–342.
Direct Link:
27
Xu D, Tsai C-J, Nussinov R ( 1997) Hydrogen bonds and salt bridges across protein–protein interfaces. Protein Eng 10: 999–1012.
28
Chalikian TV ( 2003) Hydrophobic tendencies of polar groups as a major force in molecular recognition. Biopolymers 70: 492–496.
Direct Link:
29
Cho KI, Lee K, Lee KH, Kim D, Lee D ( 2006) Specificity of molecular interactions in transient protein–protein interaction interfaces. Proteins 65: 593–606.
Direct Link:
30
Bahadur RP, Chakrabarti P, Rodier F, Janin J ( 2004) A dissection of specific and non-specific protein-protein interfaces. J Mol Biol 336: 943–955.
31
Gunasekaran K, Nussinov R ( 2007) How different are structurally flexible and rigid binding sites? Sequence and structural features discriminating proteins that do and do not undergo conformational change upon ligand binding. J Mol Biol 365: 257–273.
32
Schreiber G ( 2002) Kinetic studies of protein–protein interactions. Curr Opin Struct Biol 12: 41–47
33
Berg OG, von Hippel PH ( 1985) Diffusion-controlled macromolecular interactions. Annu Rev Biophys Chem 14: 131–160.
34
Schreiber G, Fersht AR ( 1996) Rapid, electrostatic assisted association of proteins. Nat Struct Biol 3: 427–431.
35
Vijayakumar M, Wong KY, Schreiber G, Fersht AR, Szabo A, Zhou HZ ( 1998) Electrostatic enhancement of diffusion-controlled protein–protein association: comparison of theory and experiment on barnase and barstar. J Mol Biol 278: 1015–1024.
36
Sheinerman FB, Norel R, Honig B ( 2000) Electrostatic aspects of protein–protein interactions. Curr Opin Struct Biol 10: 153–159.
37
Alsallaq R, Zhou H-X ( 2008) Electrostatic rate enhancement and transient complex of protein-protein association. Proteins 71: 320–335.
Direct Link:
38
Hanash S ( 2003) Disease proteomics. Nature 422: 226–232.
39
Ruffner H, Bauer A, Bouwmeester T ( 2007) Human protein–protein interaction networks and the value for drug discovery. Drug Discov Today 12: 709–716.
40
Hsu WT, Pang CN, Sheetal J, Wilkins MR ( 2007) Protein–protein interactions and disease: use of S. cerevisiae as a model system. Biochim Biophys Acta 1774: 838–847.
- PubMed,
- CAS
41
Goh KI, Cusick ME, Valle D, Childs B, Vidal M, Barabasi AL ( 2007) The human disease network. Proc Natl Acad Sci USA 104: 8685–8690.
42
Gregersen N, Bolund L, Bross P ( 2005) Protein misfolding, aggregation, and degradation in disease. Mol Biotechnol 31: 141–150.
43
Gregersen N ( 2006) Protein misfolding disorders: pathogenesis and intervention. J Inherit Metab Dis 29: 456–470.
44
Stefani M, Dobson CM ( 2003) Protein aggregation and aggregate toxicity: new insights into protein folding, misfolding diseases and biological evolution. J Mol Med 81: 678–699.
45
Trombetta ES, Parodi AJ ( 2003) Quality control and protein folding in the secretory pathway. Annu Rev Cell Dev Biol 19: 649–676.
46
Werner ED, Brodsky JL, McCracken AA ( 1996) Proteasome-dependent endoplasmic reticulum-associated protein degradation: an unconventional route to a familiar fate. Proc Natl Acad Sci USA 93: 13797–13801.
47
Schubert U, Anton LC, Gibbs J, Norbury CC, Yewdell JW, Bennink JR ( 2000) Rapid degradation of a large fraction of newly synthesized proteins by proteasomes. Nature 404: 770–774.
- CrossRef,
- PubMed,
- CAS,
- Web of Science®,
- ADS
48
Ulloa-Aguirre A, Janovick JA, Brothers SP, Conn PM ( 2004) Pharmacologic rescue of conformationally-defective proteins: implications for the treatment of human disease. Traffic 5: 821–837.
Direct Link:
49
Chaudhuri TK, Paul S ( 2006) Protein-misfolding diseases and chaperone-based therapeutic approaches. FEBS J 273: 1331–1349.
Direct Link:
50
Dobson CM ( 1999) Protein misfolding, evolution and disease. Trends Biochem Sci 24: 329–332.
51
Temussi PA, Masino L, Pastore A ( 2003) From Alzheimer to Huntington: why is a structural understanding so difficult? EMBO J 22: 355–361.
52
Cohen FE, Kelly JW ( 2003) Therapeutic approaches to protein–misfolding diseases. Nature 426: 905–909.
53
Prockop DJ ( 1998) What holds us together? Why do some of us fall apart? What can we do about it? Matrix Biol 16: 519–528.
54
Kielty CM ( 2006) Elastic fibres in health and disease. Expert Rev Mol Med 8: 1–23.
- CrossRef,
- PubMed
55
Butcher EC, Berg EL, Kunkel EJ ( 2004) Systems biology in drug discovery. Nat Biotechnol 22: 1253–1259.
56
Strong M, Eisenberg D ( 2007) The protein network as a tool for finding novel drug targets. Prog Drug Res 64: 191–215.
- CrossRef,
- PubMed,
- CAS
57
Kishan KV ( 2007) Structural biology, protein conformations and drug designing. Curr Protein Pept Sci 8: 376–380.
- CrossRef,
- PubMed,
- CAS
58
Huang Z ( 2002) The chemical biology of apoptosis. Exploring protein–protein interactions and the life and death of cells with small molecules. Chem Biol 9: 1059–1072.
59
Arkin MR, Wells JA ( 2004) Small-molecule inhibitors of protein–protein interactions: progressing towards the dream. Nat Rev Drug Discov 3: 301–317.
60
Chene P ( 2006) Drugs targeting protein–protein interactions. Chem Med Chem 1: 400–411.
- PubMed,
- CAS
61
Wells JA, McClendon CL ( 2007) Reaching for high-hanging fruit in drug discovery at protein–protein interfaces. Nature 450: 1001–1009.
62
Fletcher S, Hamilton AD ( 2007) Protein–protein interaction inhibitors: small molecules from screening techniques. Curr Top Med Chem 7: 922–927.
63
Veselovsky AV, Ivanov YD, Ivanov AS, Archakov AI, Lewi P, Janssen P ( 2002) Protein–protein interactions: mechanisms and modification by drugs. J Mol Recognit 15: 405–422.
Direct Link:
64
Block P, Weskamp N, Wolf A, Klebe G ( 2007) Strategies to search and design stabilizers of protein–protein interactions: a feasibility study. Proteins 68: 170–186.
Direct Link:
65
Gestwicki JE, Marinec PS ( 2007) Chemical control over protein-protein interactions: beyond inhibitors. Comb Chem High Throughput Screen 10: 667–675.
66
Vaughan TJ, Osbourn JK, Tempest PR ( 1998) Human antibodies by design. Nat Biotechnol 16: 535–539.
67
Nygren PA, Uhlen M ( 1997) Scaffolds for engineering novel binding sites in proteins. Curr Opin Struct Biol 7: 463–469.
68
Cooper WJ, Waters ML ( 2005) Molecular recognition with designed peptides and proteins. Curr Opin Chem Biol 9: 627–631.
- PubMed,
- CAS
69
Osborne SE, Ellington AD ( 1997) Nucleic acid selection and the challenge of combinatorial chemistry. Chem Rev 97: 349–370.
70
Kay BK, Kurakin AV, Hyde-DeRuyscher R ( 1998) From peptides to drugs via phage display. Drug Discov Today 3: 370–378.
71
Sidhu SS, Fairbrother WJ, Deshayes K ( 2003) Exploring protein–protein interactions with phage display. Chembiochem 4: 14–25.
Direct Link:
72
Gonzalez-Ruiz D, Gohlke H ( 2006) Targeting protein–protein interactions with small molecules: challenges and perspectives for computational binding epitope detection and ligand finding. Curr Med Chem 13: 2607–2625.
73
Zhong S, Macias AT, MacKerell AD Jr ( 2007) Computational identification of inhibitors of protein–protein interactions. Curr Top Med Chem 7: 63–82.
74
Sillerud LO, Larson RS ( 2005) Design and structure of peptide and peptidomimetic antagonists of protein–protein interaction. Curr Protein Pept Sci 6: 151–169.
75
Hershberger SJ, Lee SG, Chmielewski J ( 2007) Scaffolds for blocking protein–protein interactions. Curr Top Med Chem 7: 928–942.
76
Fletcher S, Hamilton AD ( 2005) Protein surface recognition and proteomimetics: mimics of protein surface structure and function. Curr Opin Chem Biol 9: 632–638.
77
Davis JM, Tsou LK, Hamilton AD ( 2007) Synthetic non-peptide mimetics of alpha-helices. Chem Soc Rev 36: 326–334.
78
de Vega MJ, Martín-Martínez M, González-Muniz R ( 2007) Modulation of protein–protein interactions by stabilizing/mimicking protein secondary structure elements. Curr Top Med Chem 7: 33–62.
- CrossRef,
- PubMed
79
Mammen M, Choi SK, Whitesides GM ( 1998) Polyvalent interactions in biological systems: implications for design and use of multivalent ligands and inhibitors. Angew Chem Int Ed Engl 37: 2754–2794.
Direct Link:
- Abstract
- PDF(998K)
80
Fan E, Zhang Z, Minke WE, Hou Z, Verlinde CLMJ, Hol WGJ ( 2000) High-affinity pentavalent ligands of Escherichia coli heat-labile enterotoxin by modular structure-based design. J Am Chem Soc 122: 2663–2664.
81
Gradl SN, Felix JP, Isacoff EY, Garcia ML, Trauner D ( 2003) Protein surface recognition by rational design: nanomolar ligands for potassium channels. J Am Chem Soc 125: 12668–12669.
82
Ding WD, Mitsner B, Krishnamurthy G, Aulabaugh A, Hess CD, Zaccardi J, Cutler M, Feld B, Gazumyan A, Raifeld Y, Nikitenko A, Lang SA, Gluzman Y, O'Hara B, Ellestad GA ( 1998) Novel and specific respiratory syncytial virus inhibitors that target virus fusion. J Med Chem 41: 2671–2675.
83
Fazal MA, Roy BC, Sun S, Mallik S, Rodgers KR ( 2001) Surface recognition of a protein using designed transition metal complexes. J Am Chem Soc 123: 6283–6290.
84
Sebti SM, Hamilton AD ( 2000) Design of growth factor antagonists with antiangiogenic and antitumor properties. Oncogene 19: 6566–6573.
85
Takashima H, Shinkai S, Hamachi I ( 1999) Ru(bpy)3-based artificial receptors toward a protein surface: selective binding and efficient photoreduction of cytochrome c. Chem Comm 2345–2346.
- CrossRef,
- CAS
86
Gestwicki JE, Cairo CW, Strong LE, Oetjen KA, Kiessling LL ( 2002) Influencing receptor-ligand binding mechanisms with multivalent ligand architecture. J Am Chem Soc 124: 14922–14933.
87
MacCorkle RA, Freeman KW, Spencer DM ( 1998) Synthetic activation of caspases: artificial death switches. Proc Natl Acad Sci USA 95: 3655–3660.
88
Miroy GJ, Lai Z, Lashuel HA, Peterson SA, Strang C, Kelly JW ( 1996) Inhibiting transthyretin amyloid fibril formation via protein stabilization. Proc Natl Acad Sci USA 93: 15051–15056.
89
Gordo S, Martos V, Santos E, Menéndez M, Bo C, Giralt E, de Mendoza ( 2008) J Stability and structural recovery of the tetramerization domain of p53-R337H mutant induced by a designed templating ligand. Proc Natl Acad Sci USA 105: 16426–16431.
90
Rochet JC ( 2007) Novel therapeutic strategies for the treatment of protein-misfolding diseases. Expert Rev Mol Med 9: 1–34.
- CrossRef,
- PubMed
91
Sciarretta KL, Gordon DJ, Meredith SC ( 2006) Peptide-based inhibitors of amyloid assembly. Methods Enzymol 413: 273–312.
92
Perlmutter DH ( 2002) Chemical chaperones: a pharmacological strategy for disorders of protein folding and trafficking. Pediatr Res 52: 832–836.
- PubMed
93
Arakawa T, Ejima D, Kita Y, Tsumoto K ( 2006) Small molecule pharmacological chaperones: from thermodynamic stabilization to pharmaceutical drugs. Biochim Biophys Acta 1764: 1677–1687.
- PubMed,
- CAS
94
Papp E, Csermely P ( 2006) Chemical chaperones: mechanisms of action and potential use. Handb Exp Pharmacol 172: 405–416.
- CrossRef,
- PubMed,
- CAS
95
Loo TW, Clarke DM ( 2007) Chemical and pharmacological chaperones as new therapeutic agents. Expert Rev Mol Med 9: 1–18.
- CrossRef,
- PubMed
96
Amaral MD ( 2006) Therapy through chaperones: sense or antisense? Cystic fibrosis as a model disease. J Inherit Metab Dis 29: 477–487.
97
Levine AJ ( 1997) p53, the cellular gatekeeper for growth and division. Cell 88: 323–331.
98
Sengupta S, Harris CC ( 2005) p53: traffic cop at the crossroads of DNA repair and recombination. Nat Rev Mol Cell Biol 6: 44–55.
99
Tidow H, Melero R, Mylonas E, Freund SM, Grossmann JG, Carazo JM, Svergun DI, Valle M, Fersht AR ( 2007) Quaternary structures of tumor suppressor p53 and a specific p53 DNA complex. Proc Natl Acad Sci USA 104: 12324–12329.
100
Prives C, Hall PA ( 1999) The p53 pathway. J Pathol 187: 112–126.
Direct Link:
101
Levine AJ, Hu W, Feng Z ( 2006) The P53 pathway: what questions remain to be explored? Cell Death Differ 13: 1027–1036.
102
Wang P, Reed M, Wang Y, Mayr G, Stenger JE, Anderson ME, Schwedes JF, Tegtmeyer P ( 1994) p53 domains: structure, oligomerization, and transformation. Mol Cell Biol 14: 5182–5191.
- PubMed,
- CAS
103
Milner J ( 1995) Flexibility: the key to p53 function? Trends Biochem Sci 20: 49–51.
104
Bell S, Klein C, Muller L, Hansen S, Buchner J ( 2002) p53 contains large unstructured regions in its native state. J Mol Biol 322: 917–927.
105
Joerger AC, Fersht AR ( 2007) Structure-function-rescue: the diverse nature of common p53 cancer mutants. Oncogene 26: 2226–2242.
106
Braithwaite AW, Del SG, Lu X ( 2006) Some p53-binding proteins that can function as arbiters of life and death. Cell Death Differ 13: 984–993.
107
Bullock AN, Fersht AR ( 2001) Rescuing the function of mutant p53. Nat Rev Cancer 1: 68–76.
108
Petitjean A, Mathe E, Kato S, Ishioka C, Tavtigian SV, Hainaut P, Olivier M ( 2007) Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Hum Mutat 28: 622–629.
Direct Link:
109
Zheleva DI, Lane DP, Fischer PM ( 2003) The p53-Mdm2 pathway: targets for the development of new anticancer therapeutics. Mini Rev Med Chem 3: 257–270.
- CrossRef,
- PubMed,
- CAS
110
Ariumi Y, Kaida A, Hatanaka M, Shimotohno K ( 2001) Functional cross-talk of HIV-1 Tat with p53 through its C-terminal domain. Biochem Biophys Res Commun 287: 556–561.
111
Li CJ, Wang C, Friedman DJ, Pardee AB ( 1995) Reciprocal modulations between p53 and Tat of human immunodeficiency virus type 1. Proc Natl Acad Sci USA 92: 5461–5464.
112
Hupp TR, Lane DP, Ball KL ( 2000) Strategies for manipulating the p53 pathway in the treatment of human cancer. Biochem J 352: 1–17.
113
Selivanova G, Wiman KG ( 2007) Reactivation of mutant p53: molecular mechanisms and therapeutic potential. Oncogene 26: 2243–2254.
114
Chene P ( 2003) Inhibiting the p53-MDM2 interaction: an important target for cancer therapy. Nat Rev Cancer 3: 102–109.
115
Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlott U, Lukacs C, Klein C, Fotouhi N, Liu EA ( 2004) In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303: 844–848.
116
Murray JK, Gellman SH ( 2007) Targeting protein–protein interactions: lessons from p53/MDM2. Biopolymers 88: 657–686.
Direct Link:
117
Dudkina AS, Lindsley CW ( 2007) Small molecule protein–protein inhibitors for the p53-MDM2 interaction. Curr Top Med Chem 7: 952–960.
118
Foster BA, Coffey HA, Morin MJ, Rastinejad F ( 1999) Pharmacological rescue of mutant p53 conformation and function. Science 286: 2507–2510.
119
Maurici D, Monti P, Campomenosi P, North S, Frebourg T, Fronza G, Hainaut P ( 2001) Amifostine (WR2721) restores transcriptional activity of specific p53 mutant proteins in a yeast functional assay. Oncogene 20: 3533–3540.
120
0Bykov VJ, Wiman KG ( 2003) Novel cancer therapy by reactivation of the p53 apoptosis pathway. Ann Med 35: 458–465.
121
Roth JA ( 2006) Adenovirus p53 gene therapy. Expert Opin Biol Ther 6: 55–61.

View Full Article (HTML) Get PDF (438K)

JOURNAL TOOLS

JOURNAL MENU

FIND ISSUES

FIND ARTICLES

GET ACCESS

FOR CONTRIBUTORS

ABOUT THIS JOURNAL

SPECIAL FEATURES

Knitting and untying the protein network: Modulation of protein ensembles as a therapeutic strategy

Protein Science

How to Cite

Author Information

Publication History

Funded by

ARTICLE TOOLS

References

More content like this

JOURNAL TOOLS

JOURNAL MENU

FIND ISSUES

FIND ARTICLES

GET ACCESS

FOR CONTRIBUTORS

ABOUT THIS JOURNAL

SPECIAL FEATURES

Knitting and untying the protein network: Modulation of protein ensembles as a therapeutic strategy

Protein Science

How to Cite

Author Information

Publication History

Funded by

SEARCH

SEARCH BY CITATION

ARTICLE TOOLS

References

More content like this