Your browser doesn't support javascript.
loading
Computational and experimental analysis of bioactive peptide linear motifs in the integrin adhesome.
O'Brien, Kevin T; Golla, Kalyan; Kranjc, Tilen; O'Donovan, Darragh; Allen, Seamus; Maguire, Patricia; Simpson, Jeremy C; O'Connell, David; Moran, Niamh; Shields, Denis C.
Afiliación
  • O'Brien KT; School of Medicine, University College Dublin, Dublin, Ireland.
  • Golla K; Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.
  • Kranjc T; Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.
  • O'Donovan D; Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.
  • Allen S; School of Biology and Environment Science, University College Dublin, Dublin, Ireland.
  • Maguire P; Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.
  • Simpson JC; School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland.
  • O'Connell D; Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.
  • Moran N; School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland.
  • Shields DC; Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.
PLoS One ; 14(1): e0210337, 2019.
Article en En | MEDLINE | ID: mdl-30689642
Therapeutic modulation of protein interactions is challenging, but short linear motifs (SLiMs) represent potential targets. Focal adhesions play a central role in adhesion by linking cells to the extracellular matrix. Integrins are central to this process, and many other intracellular proteins are components of the integrin adhesome. We applied a peptide network targeting approach to explore the intracellular modulation of integrin function in platelets. Firstly, we computed a platelet-relevant integrin adhesome, inferred via homology of known platelet proteins to adhesome components. We then computationally selected peptides from the set of platelet integrin adhesome cytoplasmic and membrane adjacent protein-protein interfaces. Motifs of interest in the intracellular component of the platelet integrin adhesome were identified using a predictor of SLiMs based on analysis of protein primary amino acid sequences (SLiMPred), a predictor of strongly conserved motifs within disordered protein regions (SLiMPrints), and information from the literature regarding protein interactions in the complex. We then synthesized peptides incorporating these motifs combined with cell penetrating factors (tat peptide and palmitylation for cytoplasmic and membrane proteins respectively). We tested for the platelet activating effects of the peptides, as well as their abilities to inhibit activation. Bioactivity testing revealed a number of peptides that modulated platelet function, including those derived from α-actinin (ACTN1) and syndecan (SDC4), binding to vinculin and syntenin respectively. Both chimeric peptide experiments and peptide combination experiments failed to identify strong effects, perhaps characterizing the adhesome as relatively robust against within-adhesome synergistic perturbation. We investigated in more detail peptides targeting vinculin. Combined experimental and computational evidence suggested a model in which the positively charged tat-derived cell penetrating part of the peptide contributes to bioactivity via stabilizing charge interactions with a region of the ACTN1 negatively charged surface. We conclude that some interactions in the integrin adhesome appear to be capable of modulation by short peptides, and may aid in the identification and characterization of target sites within the complex that may be useful for therapeutic modulation.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Péptidos / Integrinas / Adhesiones Focales Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: PLoS One Asunto de la revista: CIENCIA / MEDICINA Año: 2019 Tipo del documento: Article País de afiliación: Irlanda Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Péptidos / Integrinas / Adhesiones Focales Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: PLoS One Asunto de la revista: CIENCIA / MEDICINA Año: 2019 Tipo del documento: Article País de afiliación: Irlanda Pais de publicación: Estados Unidos