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PEDS Advance Access published online on March 24, 2005
Protein Engineering Design and Selection, doi:10.1093/protein/gzi004
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oupjournals.org
Received January 18, 2005
Accepted January 28, 2005

Article

G protein-coupled receptors show unusual patterns of intrinsic unfolding

Veli-Pekka Jaakola 1, Jaime Prilusky 2, Joel L. Sussman 3, and Adrian Goldman 4*

1 Institute of Biotechnology (Biocenter 3), University of Helsinki, PO Box 65, Viikinkaari 1, FIN-00014 Helsinki, Finland; Viikki Graduate School in BioSciences, PO Box 56, Viikinkaari 9, FIN-00014 Helsinki, Finland
2 Department of Biological Services, Weizmann Institute of Science, 76100 Rehovot, Israel
3 Department of Structural Biology, Weizmann Institute of Science, 76100 Rehovot, Israel
4 Institute of Biotechnology (Biocenter 3), University of Helsinki, PO Box 65, Viikinkaari 1, FIN-00014 Helsinki, Finland

* To whom correspondence should be addressed.
Adrian Goldman, E-mail: adrian.goldman{at}helsinki.fi


  Abstract

Intrinsically unstructured proteins (IUPs) or IUP-like regions often play key roles in controlling processes ranging from transcription to the cell cycle. In silico such proteins can be identified by their sequence properties; they have low hydrophobicity and high net charge. In this study, we applied the FoldIndex (http://bioportal.weizmann.ac.il/fldbin/findex) program to analyze human G protein-coupled receptors and compared them with membrane proteins of known structure and with IUPs. We show that human G protein-coupled receptor (GPCR) extramembranous domains include long (>50 residues) disordered segments, unlike membrane proteins of known structure. The predicted disorder occurred primarily in the N-terminal, C-terminal and third intracellular domain regions: 55, 69 and 56% of the human GPCRs were disordered in these regions, respectively. This increased flexibility may therefore be critical for GPCR function. Surprisingly, however, the kinds of residues used in GPCR unstructured regions were different than in hitherto-identified IUPs. The GPCR third intracellular loop domains contain very high percentages of Arg, Lys and His residues, especially Arg, but the percentage of Glu, Asp and Pro is no higher than in folded proteins. We propose that this has structural and functional consequences.

Keywords: G protein-coupled receptors; intrinsically unstructured proteins; membrane proteins; sequence prediction.
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