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Long-Range Interactions Within a Nonnative Protein
Judith Klein-Seetharaman,1*Maki Oikawa,2Shaun B. Grimshaw,3Julia Wirmer,1Elke Duchardt,1Tadashi Ueda,2Taiji Imoto,2Lorna J. Smith,3Christopher M. Dobson,3Harald Schwalbe1§
Protein folding and unfolding are coupled to a range of
biological phenomena, from the regulation of cellular activity tothe
onset of neurodegenerative diseases. Defining the nature ofthe
conformations sampled in nonnative proteins is crucial forunderstanding the origins of such phenomena. We have used a combinationof nuclear magnetic resonance (NMR) spectroscopy and site-directedmutagenesis to study unfolded states of the protein lysozyme.Extensive
clusters of hydrophobic structure exist within the wild-typeprotein
even under strongly denaturing conditions. These clustersinvolve
distinct regions of the sequence but are all disruptedby a single
point mutation that replaced residue Trp62 with Gly located
at the interface of the two major structuraldomains in the native
state. Thus, nativelike structure in thedenatured protein is
stabilized by the involvement of Trp62 in nonnative and
long-range interactions.
1 Massachusetts Institute of Technology,
Department of Chemistry, Francis Bitter Magnet Laboratory, 170 Albany
Street, Cambridge, MA 02139, USA.
2 Graduate School
of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
3 Oxford Centre for Molecular Sciences, New
Chemistry Laboratory, University of Oxford, South Parks Road, Oxford,
OX1 3QH, UK.
*
Present address: Institute for Software Research International,
Carnegie Mellon University, Wean Hall 4604, Pittsburgh, PA15213, USA.
Present address: Johann Wolfgang Goethe-University,
Center for Biological Magnetic Resonance, Institute for Organic
Chemistry,Marie-Curie-Strasse 11, D-60439 Frankfurt am Main, Germany.
Present address: Department of Chemistry, University
of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
§
To whom correspondence should be addressed. E-mail:
schwalbe{at}nmr.uni-frankfurt.de
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PERSPECTIVES
Robert L. Baldwin (1 March 2002) Science295 (5560), 1657.
[DOI: 10.1126/science.1069893] |Summary »|Full Text »|PDF »
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