Conformationally specific misfolding of an integral membrane protein

Biochemistry
K OxenoidC R Sanders

Abstract

Membrane protein misfolding is related to the etiology of many diseases, but is poorly understood, particularly from a structural standpoint. This study focuses upon misfolding of a mutant form of diacylglycerol kinase (s-DAGK), a 40 kDa homotrimeric protein having nine transmembrane segments. Preparations of s-DAGK sometimes contain a kinetically trapped misfolded population, as evidenced by lower-than-expected enzyme activity (with no accompanying change in substrate K(m)) and by the appearance of a second band in electrophoresis gels. Misfolding of s-DAGK may take place during cellular overexpression, but can also be reproduced using the purified enzyme. TROSY NMR spectra of s-DAGK as a 100 kDa complex with detergent micelles exhibit a single additional set of resonances from the misfolded form, indicating a single misfolded conformational state. The relative intensities of these extra resonances correlate with the percent reduction in enzyme activity below the maximum observed for fully folded s-DAGK. Misfolded s-DAGK exhibits a modest difference in its far-UV CD spectrum compared to the folded enzyme, consistent with a small degree of variance in secondary structural content between the two forms. However, differences in N...Continue Reading

References

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Citations

Mar 24, 2004·Journal of Molecular Biology·César FernándezKurt Wüthrich
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