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(Received for publication, June 29,
1995; and in revised form, August 25, 1995) Pigment epithelium-derived factor (PEDF), a neurite-promoting
factor, has an amino acid primary structure that is related to members
of the serine protease inhibitor (serpin) family. Controlled
proteolysis of native PEDF (50 kDa) with either trypsin, chymotrypsin,
elastase, or subtilisin yields in each case one major limited product
of 46 kDa as analyzed by SDS-polyacrylamide gel electrophoresis.
N-terminal sequence analysis of the isolated 46-kDa products indicates
a favored cleavage region located toward the C-terminal end of PEDF. A
proteolyzed PEDF protein reaction mixture reveals two overlapping
sequences: that of the N terminus of intact PEDF and that of an
internal region, consistent with cleavage of PEDF about position 382.
These data indicate that PEDF protein has a globular conformation with
one protease-sensitive exposed loop that contains the homologous
serpin-reactive site. Cleavage within the reactive-site loop of PEDF
does not cause a conformational change in the molecules (the stressed (S)
Volume 270,
Number 43,
Issue of October 27, 1995 pp. 25992-25999
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
NEUROTROPHIC ACTIVITY DOES NOT REQUIRE THE SERPIN REACTIVE LOOP
relaxed (R) transition) and results in
heat denaturation identical to its native counterpart. This lack of
conformational change is also seen upon cleavage within the
reactive-site loop of the noninhibitory serpin ovalbumin. Furthermore,
the PEDF neurite-promoting function is not lost with cleavage of the
exposed loop. Recombinant PEDF polypeptide fragments with larger
truncations from the C-terminal end show neurotrophic activity. Our
results clearly indicate that integrity of the PEDF homologous serpin
reactive center is dispensable for neurotrophic activity. Thus, the
PEDF induction of neurites must be mediated by a mechanism other than
serine protease inhibition. Altogether our data indicate that PEDF
belongs to the subgroup of noninhibitory serpins and that its
N-terminal region confers a neurite-promoting activity to the protein.
The neurotrophic active site of PEDF is separated from the serpin
reactive-site loop, not only in the primary structure, but also in the
folded protein structure.
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