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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
Chemical Compound Review

proline     pyrrolidine-2-carboxylic acid

Synonyms: CCCu, Hpro, DL-Proline, Poly-L-proline, H-DL-Pro-OH, ...
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Disease relevance of proline

  • Here we show that the amino-terminal WH1 domain, and not the polyproline-rich region, of N-WASP is responsible for its recruitment to sites of actin polymerization during Cdc42-independent, actin-based motility of vaccinia virus [1].
  • A recombinant polypeptide corresponding to the alpha(I) subunit residues 138-244 and expressed in Escherichia coli was soluble, became effectively bound to poly(L-proline) agarose and could be eluted with (Pro-Pro-Gly)10 [2].
  • Microinjection of 1-20 microM poly(L-proline) (intracellular concentration) fails to block Listeria intracellular movement or polar actin-filament assembly [3].
  • Following our previous study on the contribution of residues 25 and 26 to p53-dependent hypoxia-induced apoptosis, we found that residues 25-26 and 53-54 and the polyproline- and DNA-binding regions are also required for both gene repression and the induction of apoptosis by p53 during hypoxia [4].
  • A role for polyproline motifs in the spinal muscular atrophy protein SMN. Profilins bind to and colocalize with smn in nuclear gems [5].

High impact information on proline

  • Recent experiments demonstrating that peptides with polyalanine, polyproline, or polyglycine bind well to MHC proteins have proven that the structural requirements for binding are quite minimal [6].
  • Competitor analogs for defined T cell antigens: peptides incorporating a putative binding motif and polyproline or polyglycine spacers [7].
  • This peptide adopts a triple-helical structure that confirms the basic features determined from fiber diffraction studies on collagen: supercoiling of polyproline II helices and interchain hydrogen bonding that follows the model II of Rich and Crick [8].
  • Like agouti, ART contains a putative signal sequence and a cysteine rich carboxyl terminus, but lacks the region of basic residues and polyproline residues found in the middle of the agouti protein [9].
  • The protein exhibits sequence similarity to homeotic genes, contains several polyproline stretches, and includes a src homology 3 (SH3) domain at its very carboxyl terminus that is required for binding to Abl proteins [10].

Biological context of proline

  • The KiSS-1 cDNA encodes a predominantly hydrophilic, 164 amino acid protein with a polyproline-rich domain indicative of an SH3 ligand (binds to the homology 3 domain of the oncoprotein Src) and a putative protein kinase C-alpha phosphorylation site [11].
  • Structure of the Homer EVH1 domain-peptide complex reveals a new twist in polyproline recognition [12].
  • Analysis of the amino acid sequences of chicken and mouse aczonin indicates an organization into multiple domains, including two pairs of Cys(4) zinc fingers, a polyproline tract, and a PDZ domain and two C2 domains near the COOH terminus [13].
  • We report here that the poly(L-proline) and (Pro-Pro-Gly)10 peptide substrate-binding domain of prolyl 4-hydroxylase is distinct from the catalytic domain and consists of approximately 100 amino acids [2].
  • Yeast profilin resembles profilins from other organisms in molecular mass and in the ability to bind to polyproline, retard the rate of actin polymerization, and inhibit hydrolysis of ATP by monomeric actin [14].

Anatomical context of proline


Associations of proline with other chemical compounds

  • The side-chain pockets and conserved asparagine residues of the DR1 molecule are well-positioned to interact with peptides in the polyproline type II conformation and may restrict the range of acceptable peptide conformations [20].
  • We have generated eight mAbs (MW1-8) that bind the epitopes polyglutamine (polyQ), polyproline (polyP), or the C terminus of exon 1 in huntingtin (htt) protein [21].
  • These include two putative transmembrane domains, two sequences rich in Pro, Glu, Asp, Ser, and Thr (PEST sequences), and two polyproline-rich domains [22].
  • ALX contains several sites for potential protein-protein interaction, including an Src homology 2 (SH2) domain, four PXXP polyproline sequences, and two likely sites of tyrosine phosphorylation [23].
  • Antibodies to 2 nonviral peptides, polyhistidine and polyproline, were also overrepresented in patient sera [24].
  • The calculated TS energies and RRKM kinetic analysis indicated that peptide N-C alpha bond dissociations compete with pyrrolidine ring openings triggered by radical sites at both the N-terminal and C-terminal sides of the proline residue [25].

Gene context of proline


Analytical, diagnostic and therapeutic context of proline

  • This property may explain why the type II enzyme was not recognized earlier, as an early step in the standard purification procedure for prolyl 4-hydroxylase is affinity chromatography on a poly(L-proline) column [33].
  • CD and other optical spectroscopies have found structure in longer "random coil" peptides and have implicated polyproline II, which is a major backbone conformation in residues within loop regions of protein structures [34].
  • Circular dichroism studies on a series of monomeric and dimeric analogs revealed a strong polyproline II helical propensity in a subset of them [35].
  • The comparison of FTIR results for PHFs with collagen I gel and polyproline demonstrates that the secondary structure of PHFs is polyproline II [36].
  • We used biochemical fractionation, immunoassays and microscopy of live and fixed Acanthamoeba to determine how much profilin is bound to its known ligands: actin, membrane PIP(2), Arp2/3 complex and polyproline sequences [37].


  1. A complex of N-WASP and WIP integrates signalling cascades that lead to actin polymerization. Moreau, V., Frischknecht, F., Reckmann, I., Vincentelli, R., Rabut, G., Stewart, D., Way, M. Nat. Cell Biol. (2000) [Pubmed]
  2. Identification of a novel proline-rich peptide-binding domain in prolyl 4-hydroxylase. Myllyharju, J., Kivirikko, K.I. EMBO J. (1999) [Pubmed]
  3. Arrest of Listeria movement in host cells by a bacterial ActA analogue: implications for actin-based motility. Southwick, F.S., Purich, D.L. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  4. Genome-wide analysis of p53 under hypoxic conditions. Hammond, E.M., Mandell, D.J., Salim, A., Krieg, A.J., Johnson, T.M., Shirazi, H.A., Attardi, L.D., Giaccia, A.J. Mol. Cell. Biol. (2006) [Pubmed]
  5. A role for polyproline motifs in the spinal muscular atrophy protein SMN. Profilins bind to and colocalize with smn in nuclear gems. Giesemann, T., Rathke-Hartlieb, S., Rothkegel, M., Bartsch, J.W., Buchmeier, S., Jockusch, B.M., Jockusch, H. J. Biol. Chem. (1999) [Pubmed]
  6. Interactions between immunogenic peptides and MHC proteins. Rothbard, J.B., Gefter, M.L. Annu. Rev. Immunol. (1991) [Pubmed]
  7. Competitor analogs for defined T cell antigens: peptides incorporating a putative binding motif and polyproline or polyglycine spacers. Maryanski, J.L., Verdini, A.S., Weber, P.C., Salemme, F.R., Corradin, G. Cell (1990) [Pubmed]
  8. Crystal and molecular structure of a collagen-like peptide at 1.9 A resolution. Bella, J., Eaton, M., Brodsky, B., Berman, H.M. Science (1994) [Pubmed]
  9. Hypothalamic expression of ART, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice. Shutter, J.R., Graham, M., Kinsey, A.C., Scully, S., Lüthy, R., Stark, K.L. Genes Dev. (1997) [Pubmed]
  10. Abl-interactor-1, a novel SH3 protein binding to the carboxy-terminal portion of the Abl protein, suppresses v-abl transforming activity. Shi, Y., Alin, K., Goff, S.P. Genes Dev. (1995) [Pubmed]
  11. KiSS-1, a novel human malignant melanoma metastasis-suppressor gene. Lee, J.H., Miele, M.E., Hicks, D.J., Phillips, K.K., Trent, J.M., Weissman, B.E., Welch, D.R. J. Natl. Cancer Inst. (1996) [Pubmed]
  12. Structure of the Homer EVH1 domain-peptide complex reveals a new twist in polyproline recognition. Beneken, J., Tu, J.C., Xiao, B., Nuriya, M., Yuan, J.P., Worley, P.F., Leahy, D.J. Neuron (2000) [Pubmed]
  13. Aczonin, a 550-kD putative scaffolding protein of presynaptic active zones, shares homology regions with Rim and Bassoon and binds profilin. Wang, X., Kibschull, M., Laue, M.M., Lichte, B., Petrasch-Parwez, E., Kilimann, M.W. J. Cell Biol. (1999) [Pubmed]
  14. Purification of profilin from Saccharomyces cerevisiae and analysis of profilin-deficient cells. Haarer, B.K., Lillie, S.H., Adams, A.E., Magdolen, V., Bandlow, W., Brown, S.S. J. Cell Biol. (1990) [Pubmed]
  15. Crystal structure of tandem type III fibronectin domains from Drosophila neuroglian at 2.0 A. Huber, A.H., Wang, Y.M., Bieber, A.J., Bjorkman, P.J. Neuron (1994) [Pubmed]
  16. In vivo importance of actin nucleotide exchange catalyzed by profilin. Wolven, A.K., Belmont, L.D., Mahoney, N.M., Almo, S.C., Drubin, D.G. J. Cell Biol. (2000) [Pubmed]
  17. The epidermal growth factor receptor juxtamembrane domain has multiple basolateral plasma membrane localization determinants, including a dominant signal with a polyproline core. He, C., Hobert, M., Friend, L., Carlin, C. J. Biol. Chem. (2002) [Pubmed]
  18. Microinjected profilin affects cytoplasmic streaming in plant cells by rapidly depolymerizing actin microfilaments. Staiger, C.J., Yuan, M., Valenta, R., Shaw, P.J., Warn, R.M., Lloyd, C.W. Curr. Biol. (1994) [Pubmed]
  19. The three-dimensional structure of the cell wall glycoprotein of Chlorogonium elongatum. Shaw, P.J., Hills, G.J. J. Cell. Sci. (1984) [Pubmed]
  20. Crystallographic analysis of endogenous peptides associated with HLA-DR1 suggests a common, polyproline II-like conformation for bound peptides. Jardetzky, T.S., Brown, J.H., Gorga, J.C., Stern, L.J., Urban, R.G., Strominger, J.L., Wiley, D.C. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  21. Effects of intracellular expression of anti-huntingtin antibodies of various specificities on mutant huntingtin aggregation and toxicity. Khoshnan, A., Ko, J., Patterson, P.H. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  22. STEP61: a member of a family of brain-enriched PTPs is localized to the endoplasmic reticulum. Bult, A., Zhao, F., Dirkx, R., Sharma, E., Lukacsi, E., Solimena, M., Naegele, J.R., Lombroso, P.J. J. Neurosci. (1996) [Pubmed]
  23. The ALX Src homology 2 domain is both necessary and sufficient to inhibit T cell receptor/CD28-mediated up-regulation of RE/AP. Shapiro, M.J., Powell, P., Ndubuizu, A., Nzerem, C., Shapiro, V.S. J. Biol. Chem. (2004) [Pubmed]
  24. Selective antibody reactivity with peptides from human endogenous retroviruses and nonviral poly(amino acids) in patients with systemic lupus erythematosus. Bengtsson, A., Blomberg, J., Nived, O., Pipkorn, R., Toth, L., Sturfelt, G. Arthritis Rheum. (1996) [Pubmed]
  25. Dissecting the proline effect: dissociations of proline radicals formed by electron transfer to protonated Pro-Gly and Gly-Pro dipeptides in the gas phase. Hayakawa, S., Hashimoto, M., Matsubara, H., Turecek, F. J. Am. Chem. Soc. (2007) [Pubmed]
  26. Dual epitope recognition by the VASP EVH1 domain modulates polyproline ligand specificity and binding affinity. Ball, L.J., Kühne, R., Hoffmann, B., Häfner, A., Schmieder, P., Volkmer-Engert, R., Hof, M., Wahl, M., Schneider-Mergener, J., Walter, U., Oschkinat, H., Jarchau, T. EMBO J. (2000) [Pubmed]
  27. Identification of the endophilins (SH3p4/p8/p13) as novel binding partners for the beta1-adrenergic receptor. Tang, Y., Hu, L.A., Miller, W.E., Ringstad, N., Hall, R.A., Pitcher, J.A., DeCamilli, P., Lefkowitz, R.J. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  28. A role for the polyproline domain of p53 in its regulation by Mdm2. Berger, M., Vogt Sionov, R., Levine, A.J., Haupt, Y. J. Biol. Chem. (2001) [Pubmed]
  29. CD80 binding polyproline helical peptide inhibits T cell activation. Srinivasan, M., Lu, D., Eri, R., Brand, D.D., Haque, A., Blum, J.S. J. Biol. Chem. (2005) [Pubmed]
  30. The MEK1 proline-rich insert is required for efficient activation of the mitogen-activated protein kinases ERK1 and ERK2 in mammalian cells. Dang, A., Frost, J.A., Cobb, M.H. J. Biol. Chem. (1998) [Pubmed]
  31. Role of the Escherichia coli SbmA in the antimicrobial activity of proline-rich peptides. Mattiuzzo, M., Bandiera, A., Gennaro, R., Benincasa, M., Pacor, S., Antcheva, N., Scocchi, M. Mol. Microbiol. (2007) [Pubmed]
  32. SIT1 is a betaine/proline transporter that is activated in mouse eggs after fertilization and functions until the 2-cell stage. Anas, M.K., Lee, M.B., Zhou, C., Hammer, M.A., Slow, S., Karmouch, J., Liu, X.J., Bröer, S., Lever, M., Baltz, J.M. Development (2008) [Pubmed]
  33. Cloning, baculovirus expression, and characterization of a second mouse prolyl 4-hydroxylase alpha-subunit isoform: formation of an alpha 2 beta 2 tetramer with the protein disulfide-isomerase/beta subunit. Helaakoski, T., Annunen, P., Vuori, K., MacNeil, I.A., Pihlajaniemi, T., Kivirikko, K.I. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  34. Polyproline II structure in a sequence of seven alanine residues. Shi, Z., Olson, C.A., Rose, G.D., Baldwin, R.L., Kallenbach, N.R. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  35. Circular dichroism and nuclear magnetic resonance spectroscopic analysis of immunogenic gluten peptides and their analogs. Parrot, I., Huang, P.C., Khosla, C. J. Biol. Chem. (2002) [Pubmed]
  36. Comparative vibrational spectroscopy of intracellular tau and extracellular collagen I reveals parallels of gelation and fibrillar structure. Juszczak, L.J. J. Biol. Chem. (2004) [Pubmed]
  37. Profilin is predominantly associated with monomeric actin in Acanthamoeba. Kaiser, D.A., Vinson, V.K., Murphy, D.B., Pollard, T.D. J. Cell. Sci. (1999) [Pubmed]
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