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J. Biol. Chem., Vol. 281, Issue 45, 34465-34474, November 10, 2006

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Structure-Function Analysis and Insights into the Reduced Toxicity of Abrus precatorius Agglutinin I in Relation to Abrin^*

Ashima Bagaria¹², Kalpana Surendranath¹, Udupi A. Ramagopal^¶, Suryanarayanarao Ramakumar^||3, and Anjali A. Karande⁴

From the Department of Biochemistry, Indian Institute of Science, Bangalore 560012, India, the Department of Physics, Indian Institute of Science, Bangalore, India, the ^¶Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461, and ^||Bioinformatics Center, Indian Institute of Science, Bangalore 560012, India

Abrin and agglutinin-I from the seeds of Abrus precatorius are type II ribosome-inactivating proteins that inhibit protein synthesis in eukaryotic cells. The two toxins share a high degree of sequence similarity; however, agglutinin-I is weaker in its activity. We compared the kinetics of protein synthesis inhibition by abrin and agglutinin-I in two different cell lines and found that 200-2000-fold higher concentration of agglutinin-I is needed for the same degree of inhibition. Like abrin, agglutinin-I also induced apoptosis in the cells by triggering the intrinsic mitochondrial pathway, although at higher concentrations as compared with abrin. The reason for the decreased toxicity of agglutinin-I became apparent on the analysis of the crystal structure of agglutinin-I obtained by us in comparison with that of the reported structure of abrin. The overall protein folding of agglutinin-I is similar to that of abrin-a with a single disulfide bond holding the toxic A subunit and the lectin-like B-subunit together, constituting a heterodimer. However, there are significant differences in the secondary structural elements, mostly in the A chain. The substitution of Asn-200 in abrin-a with Pro-199 in agglutinin-I seems to be a major cause for the decreased toxicity of agglutinin-I. This perhaps is not a consequence of any kink formation by a proline residue in the helical segment, as reported by others earlier, but due to fewer interactions that proline can possibly have with the bound substrate.

Received for publication, February 24, 2006 , and in revised form, June 12, 2006.

The atomic coordinates and structure factors (code 2AMZ) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by the Department of Science and Technology, India. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² Recipient a of fellowship from the Council of Scientific and Industrial Research, India.

³ To whom correspondence may be addressed. Tel.: 91-080-2293-2718; E-mail: ramak{at}physics.iisc.ernet.in. ⁴ To whom correspondence may be addressed. Tel.: 91-080-2293-2306; E-mail: anjali{at}biochem.iisc.ernet.in.

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