The solution structure of human epidermal growth factor

Abstract

The epidermal growth factors (EGFs) are powerful mitogens for a wide variety of cells in culture; human EGF (hEGF), known as urogastrone, also inhibits gastric acid secretion in vivo. The transforming growth factors (TGF-alpha) are related to the EGF family both in sequence and activity and EGF-like sequences are often observed in a wide range of functionally unrelated proteins. Attempts to examine the structure of EGF by diffraction methods have not yet succeeded because of difficulties with crystallization. We report here a three-dimensional structure of a biologically active derivative (residues 1-48) of the 53-residue human EGF. An analysis of high resolution 1H nuclear magnetic resonance (NMR) spectra was used together with a combination of distance geometry, restrained energy minimization and restrained molecular dynamics methods. The three-dimensional structure provides a basis for understanding the properties of EGFs and for predicting the structures of homologous sequences in other proteins.

Prediction of domain organisation and secondary structure of thyroid peroxidase, a human autoantigen involved in destructive thyroiditis

“…2). The high sequence similarity between the two molecules in this region allows the structure of TPO to be predicted confidently by analogy with the NMR structure of EGF [34]. In particular this is supported by the absolute conservation of the six Cys residues that are disulphide-bonded in the EGF molecule.…”

“…In the C-terminal region of h/pTPO (742-943) the secondary structure of the EGF-like region (795-847) may be defined with confidence from the known threedimensional structure of EGF as determined by NMR [34] (see below). The 13-14 boundary coincides with the random coil N-terminus of EGF, whilst the 14-15 boundary lies in a very short ~'-strand segment near the C-terminus of EGF.…”

“…In particular this is supported by the absolute conservation of the six Cys residues that are disulphide-bonded in the EGF molecule. The structure of EGF consists of two H-strands and turns held together by a cluster of three disulphide bonds [34].…”

β‐Sheet secondary structure of an LDL receptor domain from complement factor I by consensus structure predictions and spectroscopy

“…This type of structure is analogous to other complement protein domains that possess conserved Cys residues. These structures, which include epidermal growth factor [25], the SP domain [26], the short consensus/ complement repeat [14], and the Clq globular heads [27], are all predominantly composed offl-sheet structures.…”

Simulated annealing with restrained molecular dynamics using CONGEN: Energy refinement of the NMR solution structures of epidermal and type‐α transforming growth factors

“…More than 300 EGF-like sequences have been identified as domains of larger proteins (Campbell & Bork, 1993) and many of these probably have chain folds similar to those of EGF and TGFa. Medium-resolution NMR solution structures have been described for human EGF (Cooke et al, 1987;Hommel et al, 1992) and murine EGF (Montelione et al, 1986(Montelione et al, , 1987(Montelione et al, , 1992Kohda & Inagaki, 1992a, 1992b, and for several homologous proteins including hTGFa (Kline et al, 1990;Harvey et al, 1991;Moy et al, 1993) and the EGF-like domains from bovine coagulation factor X (Selander-Sunnerhagen et al, 1992; Energy refinement of mECF and hTGFa NMR structures Ullner et al, 1992), human factor 1X (Huang et al, 1991;Baron et al, 1992), human tissue-type plasminogen activator (Smith et al, 1994), and human urokinase-type plasminogen activator (Hansen et al, 1994). X-ray crystal structures of the EGF-like domains of human E-selectin (Graves et al, 1994;Weis, 1994) and human factor Xa (Padmanabhan et al, 1993) have also been determined recently.…”