1haf Citations

High-resolution solution structure of the EGF-like domain of heregulin-alpha.

Biochemistry 35 3402-17 (1996)
Cited: 36 times
EuropePMC logo PMID: 8639490


The solution structure of the 63-residue heregulin-alpha (HRG-alpha) epidermal growth factor (EGF)-like domain, corresponding to residues 177-239 of HRG-alpha, has been determined to high resolution using data from two-dimensional and three-dimensional homo- and heteronuclear NMR spectroscopy. The structure is based on a total of 887 internuclear distance and dihedral restraints derived from data obtained using unlabeled and uniformly 15N-labeled protein samples, at pH 4.5, 20 degrees C. A total of 20 structures were calculated using a hybrid distance geometry-simulated annealing approach with the program DGII, followed by restrained molecular dynamics using the program DISCOVER. The average maximum violations are 0.12 +/- 0.01 angstroms and 1.4 +/- 0.3 degrees for distance and dihedral restraints, respectively. The backbone (N,C(alpha),C) atomic rms distribution about the mean coordinates for residues 3-23 and 31-49 is 0.29 +/- 0/07 angstroms. The N-and C-terminal residues (1-2 and 50-63) and 24-30 are disordered. Comparison of the HRG-alpha EGF-like domain structure with the previously determined structure of human EGF [Hommel et al. (1992) J. Mol. Biol. 227, 271-282] reveals a high degree of structural similarity; excluding the N-terminal region (residues 1-13), the disordered phi-loop region (residues 24-30) that contains a three-residue insertion in HRG-alpha relative to hEGF, and the disordered C-terminal region (residues 50-63), the C(alpha) alignment between the HRG-alpha and hEGF minimized mean structures has a rms difference of approximately 1 angstrom. In HRG-alpha the N-terminal residues 2-6 form a well-defined beta strand rather than being disordered as found for hEGF. This structural difference correlates with functional data which suggest that the N-terminal region of the HRG-alpha EGF-like domain is responsible for the observed receptor specificity differences between HRG-alpha and EGF.

Articles - 1haf mentioned but not cited (2)

  1. Direct binding of the EGF-like domain of neuregulin-1 to integrins ({alpha}v{beta}3 and {alpha}6{beta}4) is involved in neuregulin-1/ErbB signaling. Ieguchi K, Fujita M, Ma Z, Davari P, Taniguchi Y, Sekiguchi K, Wang B, Takada YK, Takada Y. J. Biol. Chem. 285 31388-31398 (2010)
  2. Deciphering the stepwise binding mode of HRG1β to HER3 by surface plasmon resonance and interaction map. Peess C, von Proff L, Goller S, Andersson K, Gerg M, Malmqvist M, Bossenmaier B, Schräml M. PLoS ONE 10 e0116870 (2015)

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Articles citing this publication (30)

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  9. The importance of micelle-bound states for the bioactivities of bifunctional peptide derivatives for delta/mu opioid receptor agonists and neurokinin 1 receptor antagonists. Yamamoto T, Nair P, Jacobsen NE, Davis P, Ma SW, Navratilova E, Moye S, Lai J, Yamamura HI, Vanderah TW, Porreca F, Hruby VJ. J. Med. Chem. 51 6334-6347 (2008)
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  15. Her2 activation mechanism reflects evolutionary preservation of asymmetric ectodomain dimers in the human EGFR family. Arkhipov A, Shan Y, Kim ET, Dror RO, Shaw DE. Elife 2 e00708 (2013)
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