Protein Engineering, Vol. 12, No. 11, 943-951,
November 1999
© 1999 Oxford University Press
Analysis of heregulin symmetry by weighted evolutionary tracing
University of California, UCLA–DOE Laboratory of Structural Biology and Molecular Medicine and Molecular Biology Institute, 405 Hilgard Avenue, Box 951570, Los Angeles, CA 90095-1570, USA
Heregulins are members of the protein family of EGF-like growth and differentiation factors. The primary cell-surface targets of heregulins are heterodimers of the EGF-receptor homolog HER2 with either HER3 or HER4. We used a weighted evolutionary trace analysis to identify structural features that distinguish the EGF-like domain (hrg) of heregulins from other members of the EGF family. In this analysis, each amino acid sequence is weighted according to its uniqueness and the variability in each position is assigned by an amino acid substitution matrix. Conserved residues in heregulin that are variable in other EGF-like domains are considered possible specificity-conferring residues. This analysis identifies two clusters of residues at the foot of the boot-shaped hrg domain. The residues in one cluster are recruited from the N-terminus; those in the other are from the 
-loop region and show a weak sequence similarity to the N-terminal residues at the opposite side of the boot. The remaining residues with high conservation scores distribute themselves into these two distinct surfaces on hrg. This pseudo-twofold symmetry and the presence of two distinct interfaces may reflect the preference of hrg for heterodimeric versus homodimeric HER complexes.
Keywords: evolutionary trace/HER/heregulin/receptor heterodimer/symmetry
1 Present address: Department of Math and Computer Science, Ben Gurion University, Beer-Sheva 84015, Israel
2 To whom correspondence should be addressed
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