The interactions between the TM (transmembrane) domains of many membrane proteins are important for their proper functioning. Mutations of residues into positively charged ones within TM domains were reported to be involved in many genetic diseases, possibly because these mutations affect the self- and/or hetero-assembly of the corresponding proteins. To our knowledge, despite significant progress in understanding the role of various amino acids in TM–TM interactions in vivo, the direct effect of positively charged residues on these interactions has not been studied. To address this issue, we employed the N-terminal TM domain of the aspartate receptor (Tar-1) as a dimerization model system. We expressed within the ToxR TM assembly system several Tar-1 constructs that dimerize via polar- or non-polar amino acid motifs, and mutated these by replacement with a single arginine residue. Our results have revealed that a mutation in each of the motifs significantly reduced the ability of the TMs to dimerize. Furthermore, a Tar-1 construct that contained two arginine residues was unable to correctly integrate itself into the membrane. Nevertheless, an exogenous synthetic Tar-1 peptide containing these two arginine residues was able to inhibit in vivo the marked dimerization of a mutant Tar-1 construct that contained two glutamate residues at similar positions. This indicates that hetero-assembly of TM domains can be mediated by the interaction of two oppositely charged residues, probably by formation of ion pairs. This study broadens our knowledge regarding the effect of positively charged residues on TM–TM interactions in vivo, and provides a potential therapeutic approach to inhibit uncontrolled dimerization of TM domains caused by mutations of polar amino acids.
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Research Article|
December 14 2004
Arginine mutations within a transmembrane domain of Tar, an Escherichia coli aspartate receptor, can drive homodimer dissociation and heterodimer association in vivo
Neta SAL-MAN;
Neta SAL-MAN
1Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, 76100 Israel
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Yechiel SHAI
Yechiel SHAI
1
1Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, 76100 Israel
1The Harold S. and Harriet B. Brady Professorial Chair in Cancer Research, and the author to whom correspondence should be addressed (email Yechiel.Shai@weizmann.ac.il).
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Publisher: Portland Press Ltd
Received:
June 17 2004
Revision Received:
August 23 2004
Accepted:
August 27 2004
Accepted Manuscript online:
August 27 2004
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2005
Biochem J (2005) 385 (1): 29–36.
Article history
Received:
June 17 2004
Revision Received:
August 23 2004
Accepted:
August 27 2004
Accepted Manuscript online:
August 27 2004
Citation
Neta SAL-MAN, Yechiel SHAI; Arginine mutations within a transmembrane domain of Tar, an Escherichia coli aspartate receptor, can drive homodimer dissociation and heterodimer association in vivo. Biochem J 1 January 2005; 385 (1): 29–36. doi: https://doi.org/10.1042/BJ20041022
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