Hydrophobic core repacking in a coiled-coil dimer via phage display: Insights into plasticity and specificity at a protein-protein interface

Jonathan R. Lai, John D. Fisk, Bernard Weisblum, Samuel H. Gellman

Research output: Contribution to journalArticle

19 Scopus citations


The coiled-coil, which consists of two or more interwoven amphiphilic α-helices, is formed by sequences that have a characteristic heptad repeat (abcdefg) where a and d are hydrophobic residues. Most efforts to elucidate the origins of coiled-coil pairing selectivity have focused on electrostatic interactions among side chains that flank the core (positions e and g) and on polar side chains that occur occasionally at core positions. We have used phage display to explore another source of coiled-coil specificity: steric matching among nonpolar side chains in the core. We introduced a destabilizing Leu→Ala mutation into the core of one helix in a known heterodimer and then screened a phage-based library of potential partner helices in search of compensating mutations. We identified a new heterodimer pair (30 residues/helix) that is comparable in stability to the GCN4-p1 homodimer (33 residues/helix). Furthermore, the Leu→Ala mutant shows specificity for its phage-derived partner over the original partner despite their similar sequences. These results show that a phage-based approach can provide unique insights on coiled-coil pairing preferences that should facilitate both the analysis of natural sequences and the development of specific dimerization motifs that are orthogonal to one another.

Original languageEnglish (US)
Pages (from-to)10514-10515
Number of pages2
JournalJournal of the American Chemical Society
Issue number34
Publication statusPublished - Sep 1 2004
Externally publishedYes


ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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