6los
Crystal structure of mouse PEDF in complex with heterotrimeric collagen model peptide.
Structural highlights
FunctionPEDF_MOUSE Neurotrophic protein; induces extensive neuronal differentiation in retinoblastoma cells. Potent inhibitor of angiogenesis. As it does not undergo the S (stressed) to R (relaxed) conformational transition characteristic of active serpins, it exhibits no serine protease inhibitory activity.[1] Publication Abstract from PubMedDynamic remodeling of the extracellular matrix affects many cellular processes, either directly or indirectly, through the regulation of soluble ligands; however, the mechanistic details of this process remain largely unknown. Here we propose that type I collagen remodeling regulates the receptor-binding activity of pigment epithelium-derived factor (PEDF), a widely expressed secreted glycoprotein that has multiple important biological functions in tissue and organ homeostasis. We determined the crystal structure of PEDF in complex with a disulfide cross-linked heterotrimeric collagen peptide, in which the alpha(I) chain segments-each containing the respective PEDF-binding region (residues 930 to 938)-are assembled with an alpha2alpha1alpha1 staggered configuration. The complex structure revealed that PEDF specifically interacts with a unique amphiphilic sequence, KGHRGFSGL, of the type I collagen alpha1 chain, with its proposed receptor-binding sites buried extensively. Molecular docking demonstrated that the PEDF-binding surface of type I collagen contains the cross-link-susceptible Lys930 residue of the alpha1 chain and provides a good foothold for stable docking with the alpha1(I) N-telopeptide of an adjacent triple helix in the fibril. Therefore, the binding surface is completely inaccessible if intermolecular crosslinking between two crosslink-susceptible lysyl residues, Lys9 in the N-telopeptide and Lys930, is present. These structural analyses demonstrate that PEDF molecules, once sequestered around newly synthesized pericellular collagen fibrils, are gradually liberated as collagen crosslinking increases, making them accessible for interaction with their target cell surface receptors in a spatiotemporally regulated manner. Spatiotemporal regulation of PEDF signaling by type I collagen remodeling.,Kawahara K, Yoshida T, Maruno T, Oki H, Ohkubo T, Koide T, Kobayashi Y Proc Natl Acad Sci U S A. 2020 May 26;117(21):11450-11458. doi: , 10.1073/pnas.2004034117. Epub 2020 May 8. PMID:32385162[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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