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Biological NMR Spectroscopy$
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John L. Markley and Stanley J. Opella

Print publication date: 1997

Print ISBN-13: 9780195094688

Published to Oxford Scholarship Online: November 2020

DOI: 10.1093/oso/9780195094688.001.0001

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The Role of NMR Spectroscopy in Understanding How Proteins Fold

The Role of NMR Spectroscopy in Understanding How Proteins Fold

Chapter:
(p.82) 8 The Role of NMR Spectroscopy in Understanding How Proteins Fold
Source:
Biological NMR Spectroscopy
Author(s):

C.M. Dobson

Publisher:
Oxford University Press
DOI:10.1093/oso/9780195094688.003.0014

Proteins are synthesized within the cell on ribosomes. Although there is debate as to the beginnings of folding, it is clear that the major events in the folding process of a protein occur following departure from the ribosome. Folding may involve a series of auxiliary proteins, including molecular chaperones, and for extracellular proteins may occur in part following secretion from the cell itself (Ellis, 1994). Nevertheless, many proteins also fold efficiently and correctly in isolation, for example, following transfer from a denaturing medium to a medium in which the native state is thermodynamically stable (Anfinsen, 1973). It seems most unlikely, given the improbability that folding could occur in a finite time on a random search basis (Levinthal, 1968), that the principles behind the folding process differ fundamentally in the two situations (in vivo and in vitro). Studies of the molecular basis of protein folding are therefore appropriately initiated in vitro, where physical techniques capable of providing detailed structural information can be used most readily and where folding of molecules can be examined in isolation (Evans and Radford, 1994). It has long been recognized that NMR spectroscopy, with its ability to define protein structure and dynamics in solution, is ideally suited as a technique for studying the structural transitions that take place during folding. The rapidity of folding of small proteins under most conditions, however, has until recently limited its direct application in ‘real time’ kinetic studies. Early applications of NMR in folding studies therefore included investigations of the equilibrium between folded and unfolded states, and a search for stable intermediate species (Jardetzky et al., 1972). This approach has in fact become very important in recent years with the discovery that a wide range of stable partially structured states can be generated under carefully chosen conditions, and with the development of heteronuclear NMR techniques that make possible their detailed characterisation (Dobson, 1994). The most famous of these partially folded states are known as ‘molten globules’, compact species with extensive secondary structure but Sacking persistent tertiary interactions; these are of particular interest as they appeal to be closely linked to intermediates observed in kinetic refolding experiments (Ptitsyn, 1995).

Keywords:   UV CD, fluorescence, lactalbumin, lysozyme, molten globule

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