Designed heterodimerizing leucine zippers with a ranger of pIs and stabilities up to 10(-15) M

Protein Science : a Publication of the Protein Society
J R MollC Vinson

Abstract

We have designed a heterodimerizing leucine zipper system to target a radionuclide to prelocalized noninternalizing tumor-specific antibodies. The modular nature of the leucine zipper allows us to iteratively use design rules to achieve specific homodimer and heterodimer affinities. We present circular-dichroism thermal denaturation measurements on four pairs of heterodimerizing leucine zippers. These peptides are 47 amino acids long and contain four or five pairs of electrostatically attractive g <--> e' (i, i' +5) interhelical heterodimeric interactions. The most stable heterodimer consists of an acidic leucine zipper and a basic leucine zipper that melt as homodimers in the micro (T(m) = 28 degrees C) or nanomolar (T(m) = 40 degrees C) range, respectively, but heterodimerize with a T(m) >90 degrees C, calculated to represent femtamolar affinities. Modifications to this pair of acidic and basic zippers, designed to destabilize homodimerization, resulted in peptides that are unstructured monomers at 4 microM and 6 degrees C but that heterodimerize with a T(m) = 74 degrees C or K(d(37)) = 1.1 x 10(-11) M. A third heterodimerizing pair was designed to have a more neutral isoelectric focusing point (pI) and formed a heterodimer w...Continue Reading

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