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Bioinformatics Advance Access originally published online on November 13, 2008
Bioinformatics 2009 25(2):159-162; doi:10.1093/bioinformatics/btn595
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© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Phospholipid scramblases and Tubby-like proteins belong to a new superfamily of membrane tethered transcription factors

Alex Bateman 1,*, Robert D. Finn 1, Peter J. Sims 2, Therese Wiedmer 2, Andreas Biegert 3 and Johannes Söding 3

1Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK, 2Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, 601 Elmwood Ave., Rochester, NY 14642-8626, USA and 3Gene Center and Center for Integrated Protein Science (CIPSM), Ludwig Maximilians Universität München, Feodor-Lynen-Str. 25, 81377 München, Germany

*To whom correspondence should be addressed.


  Abstract

Motivation: Phospholipid scramblases (PLSCRs) constitute a family of cytoplasmic membrane-associated proteins that were identified based upon their capacity to mediate a Ca2+-dependent bidirectional movement of phospholipids across membrane bilayers, thereby collapsing the normally asymmetric distribution of such lipids in cell membranes. The exact function and mechanism(s) of these proteins nevertheless remains obscure: data from several laboratories now suggest that in addition to their putative role in mediating transbilayer flip/flop of membrane lipids, the PLSCRs may also function to regulate diverse processes including signaling, apoptosis, cell proliferation and transcription. A major impediment to deducing the molecular details underlying the seemingly disparate biology of these proteins is the current absence of any representative molecular structures to provide guidance to the experimental investigation of their function.

Results: Here, we show that the enigmatic PLSCR family of proteins is directly related to another family of cellular proteins with a known structure. The Arabidopsis protein At5g01750 from the DUF567 family was solved by X-ray crystallography and provides the first structural model for this family. This model identifies that the presumed C-terminal transmembrane helix is buried within the core of the PLSCR structure, suggesting that palmitoylation may represent the principal membrane anchorage for these proteins. The fold of the PLSCR family is also shared by Tubby-like proteins. A search of the PDB with the HHpred server suggests a common evolutionary ancestry. Common functional features also suggest that tubby and PLSCR share a functional origin as membrane tethered transcription factors with capacity to modulate phosphoinositide-based signaling.

Contact: agb{at}sanger.ac.uk

Associate Editor: Burkhard Rost

Received on October 2, 2008; revised on November 11, 2008; accepted on November 12, 2008

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