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Volume 270, Number 29, Issue of July 21, pp. 17180-17184, 1995
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.

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(Received for publication, March 8, 1995)

From the  (1)Department of Biochemistry and (2)Center for Developmental Biology, University of Wisconsin-Madison, Madison, Wisconsin 53706

Angiogenin (ANG) promotes the formation of blood vessels in animals. This hormone is a small, monomeric protein that is homologous to bovine pancreatic ribonuclease A (RNase). ANG is a poor ribonuclease but its ribonucleolytic activity is essential for its angiogenic activity. RNase is not angiogenic. A hybrid protein was produced in which 13 residues of a divergent surface loop of ANG were substituted for the analogous 15 residues of RNase. The value of k/K for the cleavage of uridylyl(3`5`)adenosine by this hybrid protein was 20-fold less than that of RNase but 10-fold greater than that of ANG. The thermal stability of the hybrid protein was also less than that of RNase. Nevertheless, the RNase/ANG hybrid protein promotes angiogenesis in mice at least as extensively as does authentic ANG. Thus we present a protein endowed with a noncognate biological activity simply by replacing a single element of secondary structure. In addition, a 13-residue peptide corresponding to the surface loop of ANG inhibits endogenous angiogenesis in mice. These results support a model in which both a surface loop and a catalytic site are necessary for the promotion of blood vessel formation by ANG or RNase. The dissection of structure/function elements in ANG reveals a unique opportunity to develop new molecules that modulate neovascularization.

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