NDLI: Site-specific mutagenesis reveals differences in the structural bases for tight binding of RNase inhibitor to angiogenin and RNase A

Content Provider	PubMed Central
Author	Chen, Chang-zheng Shapiro, Robert
Copyright Year	1997
Abstract	RNase inhibitor (RI) binds with extraordinary affinity (K i ≈ 10−13–10−16 M) to diverse proteins in the pancreatic RNase superfamily. In the present study, the structural basis for the recognition of two RI ligands, human angiogenin (Ang) and bovine RNase A, has been investigated by site-specific mutagenesis of human RI and Ang. The RI residues examined were those that appear to form strong contacts with RNase A in the crystal structure of the porcine RI·RNase A complex [Kobe, B. & Deisenhofer, J. (1995) Nature (London) 374, 183–186] that would not be replicated in the Ang complex. Ala substitutions of five of these residues (Glu-287, Lys-320, Glu-401, Cys-408, and Arg-457) were found to have little or no effect on binding of RNase A. In contrast, replacements of Tyr-434, Asp-435, and Tyr-437 and deletion of the C-terminal residue Ser-460 substantially weakened affinity for RNase A: the losses of binding energy associated with the mutations were 5.9, 3.6, 2.6, and 3.5 kcal/mol, respectively. Thus these four residues, which are neighbors in the tertiary structure, appear to constitute a “hot spot” for the RNase A interaction. However, only one of them, Asp-435, was equally important for binding of Ang; the K i increases produced by mutations of the others were 20- to 93-fold smaller for Ang than for RNase A. Consequently, Tyr-434 plays a significant but lesser role in the Ang complex, whereas Tyr-437 and Ser-460 make only minor contributions. Ala mutations of four Ang residues (His-8, Gln-12, Asn-68, and Glu-108) that correspond to RI contacts on RNase A produced no major changes in affinity for RI. These findings indicate that RI uses largely different interactions to achieve its extremely tight binding of RNase A and Ang.
Starting Page	1761
File Format	PDF
ISSN	10916490
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	5
Volume Number	94
Language	English
Publisher	The National Academy of Sciences of the USA
Publisher Date	1997-03-04
Access Restriction	Open
Rights Holder	The National Academy of Sciences of the USA
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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