Small Retinoprotective Peptides Reveal a Receptor-binding Region on Pigment Epithelium-derived Factor
| Autor: | Jason Kenealey, Valeria Marigo, Antonella Comitato, Federica Polato, David Hoover, Jeanee Bullock, Preeti Subramanian, Laura Keehan, S. Patricia Becerra |
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| Rok vydání: | 2015 |
| Předmět: |
retina
Molecular Sequence Data cell surface receptor Peptide Biology Biochemistry Retina peptide interaction Protein structure PEDF Neurobiology Cell surface receptor Amino Acid Sequence Nerve Growth Factors protein structure Binding site Eye Proteins Molecular Biology Peptide sequence Serpins mouse chemistry.chemical_classification Binding Sites molecular modeling serpin cell death neuroprotection photoreceptor Cell Biology Biological activity Molecular biology Cell biology Molecular Docking Simulation chemistry Ectodomain Peptides Photoreceptor Cells Vertebrate |
| Zdroj: | Journal of Biological Chemistry. 290:25241-25253 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m115.645846 |
| Popis: | The cytoprotective effects of pigment epithelium-derived factor (PEDF) require interactions between an as of a yet undefined region with a distinct ectodomain on the PEDF receptor (PEDF-R). Here we characterized the area in PEDF that interacts with PEDF-R to promote photoreceptor survival. Molecular docking studies suggested that the ligand binding site of PEDF-R interacts with the neurotrophic region of PEDF (44-mer, positions 78-121). Binding assays demonstrated that PEDF-R bound the 44-mer peptide. Moreover, peptide P1 from the PEDF-R ectodomain had affinity for the 44-mer and a shorter fragment within it, 17-mer (positions 98-114). Single residue substitutions to alanine along the 17-mer sequence were designed and tested for binding and biological activity. Altered 17-mer[R99A] did not bind to the P1 peptide, whereas 17-mer[H105A] had higher affinity than the unmodified 17-mer. Peptides 17-mer, 17-mer[H105A], and 44-mer exhibited cytoprotective effects in cultured retina R28 cells. Intravitreal injections of these peptides and PEDF in the rd1 mouse model of retinal degeneration decreased the numbers of dying photoreceptors, 17-mer[H105A] being most effective. The blocking peptide P1 hindered their protective effects both in retina cells and in vivo. Thus, in addition to demonstrating that the region composed of positions 98-114 of PEDF contains critical residues for PEDF-R interaction that mediates survival effects, the findings reveal distinct small PEDF fragments with neurotrophic effects on photoreceptors. |
| Databáze: | OpenAIRE |
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