Kl. Constantine et al., MICELLE-BOUND CONFORMATIONAL PREFERENCES OF A PEPTIDE DERIVED FROM A MURINE MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-I MOLECULE, The Journal of biological chemistry, 268(30), 1993, pp. 22830-22837
Models of the micelle-bound conformation of a 17-residue major histoco
mpatibility complex-derived peptide, [Ala85]D(k)(69-85), have been det
ermined by NMR spectroscopy and simulated annealing calculations. This
peptide is a truncated, substituted version of D(k)(61-85), which is
a fragment of the murine major histocompatibility complex class I mole
cule H-2D(k). D(k)(61-85) has been shown to adopt an ordered conformat
ion required for augmentation of insulin-stimulated glucose uptake (St
agsted, J., Baase, W. A., Goldstein, A., and Olsson, L. (1991) J. Biol
. Chem. 266, 12844-12847). [Ala85]D(k)(69-85) retains full biological
activity. Thirty-eight converged NMR structures of [Ala85]D(k)(69-85)
bound to dodecyl phosphocholine micelles have been generated. The NMR-
derived models display a propensity for a type-I beta-bend involving r
esidues 73-76 and an amphipathic helical region involving residues 77-
84. CD spectra yield a helical content (8% at 20-25-degrees-C) consist
ent with transient, partial helix formation. The relative orientation
of the beta-bend region with respect to the helical region is not well
defined by the NMR data. This may reflect true heterogeneity of the m
icelle-bound conformation. The NMR structures were compared with a mod
el of [Ala85]D(k)(69-85) derived from the x-ray coordinates of the hum
an major histocompatibility complex class I allele HLA-Aw68 (Garrett,
T. P. J., Saper, M. A., Bjorkmann, P. J., Strominger, T. L., and Wiley
, D. C. (1989) Nature 342, 692-696). Structural features that are impo
rtant for the bioactivity of [Ala85]D(k)(69-85) are discussed with ref
erence to reported structure-activity relationships (Stagsted, J., Map
elli, C., Meyers, C., Matthews, B. W., Anfinsen, C. B., Goldstein, A.,
and Olsson, L. (1993) Proc. Natl. Acad. Sci. U. S. A., in press). A g
eneral description of the structural properties of the putative recept
or site(s) that are likely to be required for binding [Ala85]D(k)(6985
) is given.