A trade between similar but nonequivalent intrasubunit and intersubunit contacts in Cro dimer evolution

Tracey Newlove, Kelly R. Atkinson, Laura O. Van Dorn, Matthew H.J. Cordes

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10 Scopus citations


The homodimeric λ Cro protein has a "ball-and-socket" interface that includes insertion of an aromatic side chain, Phe 58, from each subunit into a cavity in the hydrophobic core of the other subunit. This overlap between the subunit core and dimer interface hypothetically explains the strong dimerization and weak monomer stability of λ Cro in comparison to homologues. According to a model developed here and in a previous study [LeFevre, K. R., and Cordes, M. H. (2003) Proc. Natl. Acad. Sci. U.S.A. 100, 2345-2350], the socket cavity evolved in part by replacement of a buried tryptophan in an ancestral stable monomer with a smaller side chain (Ala 33 in λ Cro). The resulting core defect was in effect repaired by insertion of a different side chain (Phe 58) from a second subunit, generating the ball and socket. Consistent with such an evolutionary trade between intrasubunit and intersubunit interactions, we showed in the previous study that restoration of the ancestral Trp 33 in λ Cro stabilized the monomer and reduced the extent of dimerization. Here, we report the solution structure of a stable λ Cro monomer containing the Ala33Trp mutation, which confirms that the restored tryptophan fulfills its ancestral role as a core side chain, filling part of the socket cavity occupied by Phe 58 in the wild-type dimer. The structure also reveals, however, that the cavity is not completely filled by Trp 33, suggesting that its formation could have involved multiple mutations that reduced side chain volume. We offer suggestive evidence of a role of mutations at a second position.

Original languageEnglish (US)
Pages (from-to)6379-6391
Number of pages13
Issue number20
StatePublished - May 23 2006

ASJC Scopus subject areas

  • Biochemistry


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