umu.sePublikationer
Ändra sökning
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
Multivariate design and evaluation of a set of RGRPQ-derived innate immunity peptides
Umeå universitet, Medicinsk fakultet, Odontologi.
Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
Umeå universitet, Medicinsk fakultet, Odontologi, Kariologi.
Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
Visa övriga samt affilieringar
2006 (Engelska)Ingår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 281, nr 22, s. 15164-15171Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Oral commensal Streptococcus gordonii proteolytically cleave the salivary PRP-1 polypeptide into an RGRPQ innate peptide. The Arg and Gln termini are crucial for RGRPQ-mediated ammonia production and proliferation by S. gordonii SK12 and adhesion inhibition and desorption by Actinomyces naeslundii T14V, respectively. Here we have applied (i) a multivariate approach using RGRPQ-related peptides varied at amino acids 2, 3, and 4 simultaneously and (ii) size and N- and C-terminal modifications of RGRPQ to generate structure activity information. While the N-terminal arginine motif mediated ammonia production independent of peptide size, other responses required more or less full-length peptide motifs. The motifs for adhesion inhibition and desorption were the same. The adhesion and proliferation motifs required similarly a hydrophobic/low polarity amino acid 4 but differentially a hydrophilic or hydrophobic character of amino acids 2/3, respectively; polar peptides with small/hydrophilic and hydrophilic amino acids 2 and 3, respectively, had high adhesion inhibition/desorption activity, and lipophilic peptides with large/hydrophobic amino acids 2 and 3 had high proliferation activity. Accordingly, while RIWWQ had increased proliferation but abolished adhesion/desorption activity, peptides designed with hydrophilic amino acids 2 and 3 were predicted to behave in the opposite way. Moreover, a RGRPQ mimetic for all three responses should mimic small hydrophilic, large nitrogen-containing, and hydrophobic/low polarity amino acids 2, 3, and 4, respectively. Peptides fulfilling these criteria were 1-1.6-fold improved in all three responses. Thus, both mimetics and peptides with differential proliferation and adhesion activities may be generated for evaluation in biofilm models.

Ort, förlag, år, upplaga, sidor
2006. Vol. 281, nr 22, s. 15164-15171
Nyckelord [en]
Actinomyces/immunology/pathogenicity, Amino Acid Sequence, Ammonia/metabolism, Bacterial Adhesion/drug effects, Drug Design, Humans, Immunity; Natural, Oligopeptides/chemistry/*immunology/pharmacology, Peptide Library, Peptides/chemistry/immunology, Quantitative Structure-Activity Relationship, Saliva/immunology, Salivary Proteins/chemistry/immunology, Streptococcus/immunology/pathogenicity
Identifikatorer
URN: urn:nbn:se:umu:diva-10654DOI: doi:10.1074/jbc.M511727200PubMedID: 16595685OAI: oai:DiVA.org:umu-10654DiVA, id: diva2:150325
Anmärkning
Kemi, kemometri, odontologi, kariologiTillgänglig från: 2007-04-19 Skapad: 2007-04-19 Senast uppdaterad: 2018-06-09Bibliografiskt granskad
Ingår i avhandling
1. Adhesion-related interactions of Actinomyces and Streptococcus biofilm bacteria
Öppna denna publikation i ny flik eller fönster >>Adhesion-related interactions of Actinomyces and Streptococcus biofilm bacteria
2006 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Adhesion of bacteria is a key event in biofilm formation and is mediated by bacterial adhesins recognising host or bacterial partner receptors. In oral biofilm formation, primary Actinomyces and Streptococcus colonizers adhere to salivary pellicle proteins such as proline-rich proteins (PRPs) as well as to mucosal surfaces. Subsequently, Actinomyces and Streptococcus strains and other bacteria, such as Veillonella, Fusobacterium and Porphyromonas, adhere to each other. The nature of this community is highly important for the health or disease status, although specific pathogenic species may also have been implicated.

The aim of this thesis was to study key players in early oral colonisation, Actinomyces and Streptococcus species, and more specifically the nature of their adhesins and ligands. A further aim was to study the function of the salivary PRP proteins and an innate peptide derived thereof on bacterial adhesion, proliferation and regulation of pH, i.e. key factors in biofilm formation.

In paper I and II, adhesion, proliferation and pH affecting features of the RGRPQ (arginine-glycine-arginine-proline-glutamine) peptide, derived from PRP-1, were demonstrated. By use of an alanine-scan (I), motifs for adhesion inhibition and desorption of Actinomyces naeslundii, and proliferation stimulation, ammonia production and inhibition of sucrose induced pH drop by Streptococcus gordonii were indicated. The RGRPQ peptide also stimulated S. gordonii colonisation in vivo. In paper II, a more sophisticated quantitative structure-activity relationship (QSAR) study, using statistical molecular design (SMD) and multivariate modelling (partial least squares projections to latent structures, PLS), further narrowed down the RGRPQ peptide motifs. The R and Q amino acids were crucial for activity. For proliferation a hydrophobic and large size third position amino acid was crucial, while adhesion inhibition and desorption needed a small hydrophilic second position amino acid. All functions depended on a low polarity hydrophobic fourth position. Accordingly, activities could be optimized separately, with decreased function in the others.

In paper III and IV, focus was on the bacterial adhesins and their binding epitopes. The genes for FimA major subunit proteins of type-2 fimbriae were sequenced from A. naeslundii genospecies 1 and 2 and Actinomyces odontolyticus, each with unique carbohydrate binding specificities (III). Three major subtypes of FimA proteins were found that correlated with binding specificity, including a novel fimA gene in A. odontolyticus. All subtypes contained a pilin, LPXTG and E box motif. In paper IV, multiple PRP binding patterns for Actinomyces and Streptococcus strains were mapped using a hybrid peptide construct. The two most deviating binding groups deviated in type-1 fimbriae mediated binding to milk and saliva protein ligands.

In conclusion, differences in bacterial adhesins and their ability to utilise salivary proteins may render bacteria tropism for different niches. Peptides derived from protein receptors, such as RGRPQ, may be important modulators of biofilm formation, giving commensal bacteria a competitive edge in the bacterial community.

Ort, förlag, år, upplaga, sidor
Umeå: Odontologi, 2006. s. 45
Serie
Umeå University odontological dissertations, ISSN 0345-7532 ; 92
Nyckelord
biofilm, Actinomyces, Streptococcus, adhesion
Nationell ämneskategori
Odontologi
Identifikatorer
urn:nbn:se:umu:diva-860 (URN)91-7264-111-8 (ISBN)
Disputation
2006-09-29, Sal B, Tandläkarhögskolan 9 tr, 90187 Umeå, Umeå, 13:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2006-09-08 Skapad: 2006-09-08 Senast uppdaterad: 2009-10-01Bibliografiskt granskad

Open Access i DiVA

Fulltext saknas i DiVA

Övriga länkar

Förlagets fulltextPubMed

Personposter BETA

Drobni, MirvaAlmqvist, FredrikStrömberg, Nicklas

Sök vidare i DiVA

Av författaren/redaktören
Drobni, MirvaAlmqvist, FredrikStrömberg, Nicklas
Av organisationen
OdontologiKemiKariologi
I samma tidskrift
Journal of Biological Chemistry

Sök vidare utanför DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetricpoäng

doi
pubmed
urn-nbn
Totalt: 324 träffar
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf