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Author
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Topic: Negative Design: Eliminating Nonfunctionality
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Paul A. Nelson
Member
Member # 26
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posted 29. April 2002 10:53
This paper, from the latest Nature Structural Biology, sounds very much like what John Bracht has in mind:
Published online: 8 April 2002, DOI:10.1038/nsb784
May 2002 Volume 9 Number 5 pp 381 - 388
A protein sequence that can encode native structure by disfavoring alternate conformations
W. Christian Wigley1, Michael J. Corboy1, Todd D. Cutler1, Patrick H. Thibodeau1, 2,
Jorge Oldan3, Min Goo Lee4, Josep Rizo5, John F. Hunt3 & Philip J. Thomas1
Abstract:
The linear sequence of amino acids contains all the necessary information for a protein to fold into its unique three-dimensional structure. Native protein sequences are known to accomplish this by promoting the formation of stable, kinetically accessible structures. Here we describe a Pro residue in the center of the third transmembrane helix of the cystic fibrosis transmembrane conductance regulator that promotes folding by a distinct mechanism: disfavoring the formation of a misfolded structure. The generality of this mechanism is supported by genome-wide transmembrane sequence analyses. Furthermore, the results provide an explanation for the increased frequency of Pro residues in transmembrane -helices. Incorporation by nature of such 'negative folding determinants', aimed at preventing the formation of off-pathway structures, represents an additional mechanism by which folding information is encoded within the evolved sequences of proteins.
1. Department of Physiology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9040, USA.
2. Department of Molecular Biophysics Graduate Program, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9040, USA.
3. Department of Biological Sciences, Columbia University, New York, New York 10027, USA.
4. Department of Pharmacology and BK21 Project for Medical Sciences, Yonsei University College of Medicine, 120-752, 134 Sinchon-dong, Seodaemun-gu, Seoul, Korea.
5. Departments of Biochemistry and Pharmacology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9041, USA.
Correspondence should be addressed to P J Thomas. e-mail: Philip.Thomas@UTSouthwestern.edu
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Art
Member
Member # 179
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posted 29. April 2002 14:39
Paul related:
quote:
This paper, from the latest Nature Structural Biology, sounds very much like what John Bracht has in mind:
Published online: 8 April 2002, DOI:10.1038/nsb784
May 2002 Volume 9 Number 5 pp 381 - 388
A protein sequence that can encode native structure by disfavoring alternate conformations
This paper adds weight to the proposition that chaperonins may be active players in "negative design". This follows from the recollection that a crucial class of chaperonins (cyclophilins) is needed to rapidly sample and "find" the proper cis/trans configuration around proline-containing peptide bonds. Without these enzymes, prolines would actually be detrimental to normal folding. And suitably-sited prolines would not be very useful in "guiding" the proper folding pathway by eliminating unfruitful ones.
This in turn should cause one to reconsider the claim that chaperonins in and of themselves do not contribute conformational "information" to the folding process. I think a good case can be made for the opposite with cyclophilins and peptide disulfide isomerases, and that there is some potential in incorporating these enzymes into models dealing with negative design.
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