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Volume 271, Number 38, Issue of September 20, 1996 pp. 23284-23288
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Evidence for -Helical Conformation of an Essential N-terminal Region in the Human Bcl2 Protein

(Received for publication, January 25, 1996, and in revised form, June 7, 1996)

Lillian C. Lee , John J. Hunter ^¶ , Anwer Mujeeb , Christoph Turck ^'' and Tristram G. Parslow ^¶

From the Departments of  Pathology, ^¶ Microbiology and Immunology, and  Pharmaceutical Chemistry and the ^'' Howard Hughes Medical Institute, University of California, San Francisco, California 94143

A region occupying approximately 24 amino acids near the N terminus of human Bcl2 is essential for this cytoplasmic membrane protein's ability to inhibit apoptosis. Systematic mutagenesis of this N-terminal region indicates that only five hydrophobic and aromatic residues within it are specifically required for function. Computerized secondary structure prediction, together with circular dichroism spectroscopy of synthetic peptides, indicates that the region encompassing these five residues has the propensity to take on an -helical conformation in the presence of SDS micelles, which presumably mimic the hydrophobic surfaces of cellular membranes or polypeptides. The five critical residues are predicted to be clustered on one face of this putative helix, where they might serve to mediate protein-protein contacts involved in the multimerization of Bcl2 or in the interaction of Bcl2 with other, as yet unidentified components of the apoptotic pathway. Apparent structural homologues of this helical motif are also present in at least some other anti-apoptotic proteins from the Bcl2 family but not in those family members that tend to potentiate, rather than inhibit, apoptosis.

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