A study on a common sequence motif in membrane proteins, called a …

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• Acknowledgements
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Biology Articles » Biophysics » Medical Biophysics » Transmembrane glycine zippers: Physiological and pathological roles in membrane proteins

Abstract

- Transmembrane glycine zippers: Physiological and pathological roles in membrane proteins

Sanguk Kim ^* , Tae-Joon Jeon , Amit Oberai ^*, Duan Yang ^*, Jacob J. Schmidt , and James U. Bowie ^*, 

^*Department of Chemistry and Biochemistry and UCLA-DOE Institute for Genomics and Proteomics and Department of Bioengineering, University of California, Los Angeles, CA 90095

Edited by Donald M. Engelman, Yale University, New Haven, CT and approved August 12, 2005 (received for review February 13, 2005)

We have observed a common sequence motif in membrane proteins, which we call a glycine zipper. Glycine zipper motifs are strongly overrepresented and conserved in membrane protein sequences, and mutations in glycine zipper motifs are deleterious to function in many cases. The glycine zipper has a significant structural impact, engendering a strong driving force for right-handed packing against a neighboring helix. Thus, the presence of a glycine zipper motif leads directly to testable structural hypotheses, particularly for a subclass of glycine zipper proteins that form channels. For example, we suggest that the membrane pores formed by the amyloid- peptide in vitro are constructed by glycine zipper packing and find that mutations in the glycine zipper motif block channel formation. Our findings highlight an important structural motif in a wide variety of normal and pathological processes.

amyloid- | membrane channel | membrane protein structure | prion | transmembrane helix

PNAS | October 4, 2005 | vol. 102 | no. 40 | 14278-14283. Copyright 2005 by the National Academy of Sciences.

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More than 13 structures a day are currently being deposited in the Protein Data Bank (1), and structural genomics centers have been created to obtain structures even faster [such as the National Institute of General Medical Sciences (NIGMS) Protein Structure Initiative, www.nigms.nih.gov/psi]. In this assault on protein structure, however, technical challenges have left membrane proteins far behind. Membrane protein structures are currently being solved at 0.2% of the pace of soluble proteins (2). Thus, membrane protein biochemists are relatively starved for structural insight into these key proteins. In the absence of dramatic technical improvements, alternatives to experimental structure determination are needed.

Here, we describe a transmembrane (TM) sequence motif, the glycine zipper, that can lead directly to structural models for many membrane proteins. The most significant glycine zipper sequence patterns are (G,A,S)XXXGXXXG and GXXXGXXX(G,S,T). These patterns contain a GXXXG motif, which is known to be important in TM helix homodimers where the Gly faces are in direct contact (3-5). The GXXXG sequence pattern is statistically overrepresented in membrane proteins in general, not just in TM homodimers (4). Nevertheless, the structural role of the GXXXG pattern in other types of TM helix packing interactions has not been elucidated. We find that the addition of an appropriately spaced small residue, as found in the glycine zipper, leads to a distinct preference for right-handed packing against a heterologous helix surface. Thus, the presence of a glycine zipper generates a strong helix packing prediction, particularly for homooligomeric channel proteins, providing a structural foundation for hypothesis-driven investigations