PEDF and the serpins: phylogeny, sequence conservation, and functional domains.
Pigment epithelium derived factor (PEDF) is non-inhibitory serpin with neurotrophic and antiangiogenic functions. In this study, we have assembled PEDF sequences for 9 additional species by data base mining and performed cross-species alignment for 14 PEDF sequences to identify conserved structural domains. We found evolutionary conservation of a leader sequence, a single C-terminal glycosylation site, collagen-binding residues, and four specific conserved PEDF peptides. The C-terminus, 384--415 and an N-terminal region 78--95, show close homology with many other serpins, and there is strong conservation of 39 of 51 consensus key residues involved in serpin structure and function. Two peptide regions, 40--67 and 277--301, are unique to PEDF but conserved in all species. Conserved residues at the N-terminus, helix d (hD), and helix A (hA) of PEDF form a structure similar to the heparin-binding groove of other serpins. We identified a motif in PEDF that is homologous to the nuclear localization signals of other proteins. A bitopographical localization of PEDF was confirmed by immunocytochemistry and Western blots. Our results suggest that secretion is required for PEDF's activity, that PEDF can migrate to the nucleus, and that PEDF has structural and functional features more common with inhibitory serpins.
Tombran-Tink
Joyce
J
Division of Pharmaceutical Sciences, University of Missouri-Kansas City, Kansas City, MO 64110, USA. jttink@aol.com
Aparicio
Samuel
S
Xu
Xuming
X
Tink
Amber R
AR
Lara
Nuria
N
Sawant
Supriya
S
Barnstable
Colin J
CJ
Zhang
Samuel Shao-Min
SS
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D016384:Consensus Sequence; D017124:Conserved Sequence; D019143:Evolution, Molecular; D005136:Eye Proteins / Q000737:chemistry*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009414:Nerve Growth Factors / Q000737:chemistry*; D010802:Phylogeny; D010857:Pigment Epithelium of Eye / Q000166:cytology; D021382:Protein Sorting Signals; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D015843:Serpins / Q000737:chemistry* / Q000145:classification; D013329:Structure-Activity Relationship; D000099174:Pigment Epithelium-Derived Factor
D005136:Eye Proteins; D009414:Nerve Growth Factors; D021382:Protein Sorting Signals; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor