Identifying the PEDF-receptor binding site on PEDF

Tuesday, October 09, 2012 — Poster Session I
1:00 p.m. – 3:00 p.m	Natcher Conference Center, Building 45	NEI	BIOCHEM-4

Authors

• JD Kenealey
• D Hoover
• SP Becerra

Abstract

Pigment epithelium-derived factor (PEDF) is a non-inhibitory serpin that has a broad spectrum of biologic activity spanning from neuroprotective to anti-tumorigenic. PEDF’s neuroprotective activity has been shown to be induced by interactions with the exodomain of the PEDF receptor (PEDF-R) involved in neuroprotection. However, the region on PEDF that binds to the receptor has not been ascertained. Using several binding assays the 44-mer, region of PEDF (V78-T121) previously described as neurotrophically active, binds specifically and selectively (Kd ~ 70 nM) to a PEDF-R exodomain peptide (P1). However, the anti-angiogenic and anti-tumorigenic 34-mer peptide (D44-N77) lacked binding affinity for P1. Trimming the 44-mer to 17 amino acids (Q98-S114) retained binding specificity to P1 (Kd ~ 500 nM). Additionally, altering each residue in the 17-mer to alanine reveals two key amino acids for this interaction. The R99A change was necessary for 17-mer:P1 binding, and the other H105A allowed for approximately 10 fold tighter binding. This study maps a novel neurotrophic region of PEDF (17-mer), as a key component for binding to the PEDF-R, and identifies key amino acids involved in the interaction.

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