Evaluation of diverse ?/?-backbone patterns for functional ?-helix mimicry: analogues of the Bim BH3 domain.

ABSTRACT: Peptidic oligomers that contain both ?- and ?-amino acid residues, in regular patterns throughout the backbone, are emerging as structural mimics of ?-helix-forming conventional peptides (composed exclusively of ?-amino acid residues). Here we describe a comprehensive evaluation of diverse ?/?-peptide homologues of the Bim BH3 domain in terms of their ability to bind to the BH3-recognition sites on two partner proteins, Bcl-x(L) and Mcl-1. These proteins are members of the anti-apoptotic Bcl-2 family, and both bind tightly to the Bim BH3 domain itself. All ?/?-peptide homologues retain the side-chain sequence of the Bim BH3 domain, but each homologue contains periodic ?-residue ? ?(3)-residue substitutions. Previous work has shown that the ??????? pattern, which aligns the ?(3)-residues in a 'stripe' along one side of the helix, can support functional ?-helix mimicry, and the results reported here strengthen this conclusion. The present study provides the first evaluation of functional mimicry by ??? and ???? patterns, which cause the ?(3)-residues to spiral around the helix periphery. We find that the ???? pattern can support effective mimicry of the Bim BH3 domain, as manifested by the crystal structure of an ?/?-peptide bound to Bcl-x(L), affinity for a variety of Bcl-2 family proteins, and induction of apoptotic signaling in mouse embryonic fibroblast extracts. The best ???? homologue shows substantial protection from proteolytic degradation relative to the Bim BH3 ?-peptide.

SUBMITTER: Boersma MD 

PROVIDER: S-EPMC3364022 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature