title: Small Retinoprotective Peptides Reveal a Receptor-binding Region on Pigment Epithelium-derived Factor.
abstract: 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.
authors: From the National Eye Institute and.
authors: Jason
authors: J
authors: Kenealey
authors: From the National Eye Institute and.
authors: Preeti
authors: P
authors: Subramanian
authors: the Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy, and.
authors: Antonella
authors: A
authors: Comitato
authors: From the National Eye Institute and the Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, D. C. 20057.
authors: Jeanee
authors: J
authors: Bullock
authors: From the National Eye Institute and.
authors: Laura
authors: L
authors: Keehan
authors: From the National Eye Institute and.
authors: Federica
authors: F
authors: Polato
authors: the Center for Information Technology, National Institutes of Health, Bethesda, Maryland 20892.
authors: David
authors: D
authors: Hoover
authors: the Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy, and.
authors: Valeria
authors: V
authors: Marigo
authors: From the National Eye Institute and becerrap@nei.nih.gov.
authors: S Patricia
authors: SP
authors: Becerra
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D005136:Eye Proteins / Q000378:metabolism*; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D009414:Nerve Growth Factors / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism*; D012160:Retina / Q000187:drug effects* / Q000378:metabolism; D015843:Serpins / Q000378:metabolism*; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D005136:Eye Proteins; D009414:Nerve Growth Factors; D010455:Peptides; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor
keywords: cell death; cell surface receptor; molecular modeling; mouse; neuroprotection; peptide interaction; photoreceptor; protein structure; retina; serpin