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The study of conformational states of proteins by nuclear magnetic resonance.

ABSTRACT: By the use of examples, mainly of rather rigid proteins, we hope to have shown that conformational analysis of proteins is a problem that is not simply related to the conformational analysis of small molecules. The primary difficulties with proteins are (1) the multitude of possible conformers, (2) the complex dynamical behaviour and (3) the degree of co-operativity within the molecules. Any experimentally derived structural description of a protein is an attempt to represent some average of a complex time dependence. N.m.r. techniques have now reached the point where it is possible to use them to describe many detailed structural features of small globular proteins in solution and to detect and to describe conformational changes in such proteins. In addition, analysis is becoming possible of much less ordered regions of polypeptides, such as are found in less compact proteins, of for example myosin, histones and virus coat proteins, or in denatured states. The limits to the detailed conformational analysis of such proteins are likely to be ones of reality rather than method but the description of the properties shown in Table 1 is by its very nature an extremely important problem in conformational analysis of dynamic macromolecules.

SUBMITTER: Campbell ID

PROVIDER: S-EPMC1152695 | biostudies-other | 1985 Oct

REPOSITORIES: biostudies-other

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Project description:Amyloid aggregates of a C-truncated Y145Stop mutant of human prion protein, huPrP23-144, associated with a heritable amyloid angiopathy, have previously been shown to contain a compact, relatively rigid, and beta-sheet-rich approximately 30-residue amyloid core near the C-terminus under physiologically relevant conditions. In contrast, the remaining huPrP23-144 residues display considerable conformational dynamics, as evidenced by the absence of corresponding signals in cross-polarization (CP)-based solid-state NMR (SSNMR) spectra under ambient conditions and their emergence in analogous spectra recorded at low temperature on frozen fibril samples. Here, we present the direct observation of residues comprising the flexible N-terminal domain of huPrP23-144 amyloid by using 2D J-coupling-based magic-angle spinning (MAS) SSNMR techniques. Chemical shifts for these residues indicate that the N-terminal domain is effectively an ensemble of protein chains with random-coil-like conformations. Interestingly, a detailed analysis of signal intensities in CP-based 3D SSNMR spectra suggests that non-negligible molecular motions may also be occurring on the NMR time scale within the relatively rigid core of huPrP23-144 amyloid. To further investigate this hypothesis, quantitative measurements of backbone dipolar order parameters and transverse spin relaxation rates were performed for the core residues. The observed order parameters indicate that, on the submicrosecond time scale, these residues are effectively rigid and experience only highly restricted and relatively uniform motions similar to those characteristic for well-structured regions of microcrystalline proteins. On the other hand, significant variations in magnitude of transverse spin relaxation rates were noted for residues present at different locations within the core region and correlated with observed differences in spectral intensities. While interpreted only qualitatively at the present time, the extent of the observed variations in transverse relaxation rates is consistent with the presence of relatively slow, microsecond-millisecond time scale chemical exchange type phenomena within the huPrP23-144 amyloid core.

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The study of conformational states of proteins by nuclear magnetic resonance.

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