Abstract:
:Human type-alpha transforming growth factor (hTGF alpha) is a small mitogenic protein containing 50 amino acids and three disulfide bonds. It has both sequence and structural homology with epidermal growth factor (EGF). While the three-dimensional structures of hTGF alpha and other EGF-like proteins have been studied extensively, relatively little is known about conformational dynamics of these molecules. In this paper we describe nuclear relaxation measurements which probe the molecular dynamics of hTGF alpha in aqueous solution at neutral pH. In order to characterize conformational dynamics of hTGF alpha on both the fast (i.e., sub-nanosecond) and intermediate nitrogen-15 chemical-exchange (i.e., microsecond) time scales, we measured nitrogen-15 relaxation parameters at pH 7.1 +/- 0.1 and a temperature of 30 +/- 0.5 degrees C. Measurements of nitrogen-15 longitudinal (R1) and transverse (R2) relaxation rates, and 1H-15N heteronuclear NOE effects, were then interpreted using an extended Lipari-Szabo analysis [Lipari, G., & Szabo, A. (1982) J. Am. Chem. Soc. 104, 4546-4559; Clore, G. M., Szabo, A., Bax, A., Kay, L. E., Driscoll, P. C., & Gronenborn, A. M. (1990) J. Am. Chem. Soc. 112, 4989-4991] to provide estimates of the locations and amplitudes of fast internal motions and the locations of nitrogen-15 chemical-exchange line broadening. These results demonstrate that, under conditions of pH and temperature at which it is tightly bound by the EGF receptor, hTGF alpha is a highly dynamic molecule. Indeed, some 40% of the backbone amide groups of hTGF alpha, including many at the interface between the two subdomains, exhibit significant nitrogen-15 chemical-exchange line broadening indicative of interconversions between multiple protein conformations on the microsecond time scale. The distribution of these sites on the three-dimensional protein structure suggests that these dynamic fluctuations are due to (i) partial unfolding of the core beta-sheet, (ii) hinge-bending motions between the N- and C-terminal subdomains, and/or (iii) disulfide bond isomerization in the solution structure of hTGF alpha at neutral pH.
journal_name
Biochemistryjournal_title
Biochemistryauthors
Li YC,Montelione GTdoi
10.1021/bi00008a003subject
Has Abstractpub_date
1995-02-28 00:00:00pages
2408-23issue
8eissn
0006-2960issn
1520-4995journal_volume
34pub_type
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