PMID:14979727

Citation	Sal-Man, N, Gerber, D and Shai, Y (2004) The composition rather than position of polar residues (QxxS) drives aspartate receptor transmembrane domain dimerization in vivo. Biochemistry 43:2309-13
Abstract	Transmembrane (TM) helix association is an important process affecting the function of many integral membrane proteins. Consequently, aberrations in this process are associated with diseases. Unfortunately, our knowledge of the factors that control this oligomerization process in the membrane milieu is limited at best. Previous studies have shown a role for polar residues in the assembly of synthetic peptides in vitro and the association of de novo-designed TM helices in vivo. Here we examined, for the first time, the involvement of polar residues in the dimerization of a biological TM domain in its natural environment. We analyzed both the involvement of polar residues in the dimerization process and whether their influence is position-dependent. For this purpose, we used the TM domain of the Escherichia coli aspartate receptor (Tar) and 10 single and double mutants. Polar to nonpolar mutations in the sequence demonstrated the role of the QxxS motif in the dimerization of the Tar TM domain. Moreover, creating a GxxxG motif, instead of the polar motif, almost completely abolished dimerization. Swapping positions between two wild-type polar residues did not affect dimerization, implying a similar contribution from both positions. Interestingly, mutants that contain two identical strong polar residues, EE and QQ, demonstrated a substantially higher level of dimerization than a QE mutant, although all three TM domains contain two strong polar residues. This result suggests that, in addition to the polarity of the residues, the formation of symmetric bonds also plays a role in dimer stability. The results of this study may facilitate a rational modulation of membrane protein function for therapeutic purposes.
Links	PubMed Online version:10.1021/bi0356294
Keywords	Amino Acid Motifs/genetics; Amino Acid Sequence; Amino Acid Substitution/genetics; Aspartic Acid/chemistry; Bacterial Proteins/biosynthesis; Bacterial Proteins/genetics; Chemoreceptor Cells; DNA-Binding Proteins/biosynthesis; DNA-Binding Proteins/genetics; Dimerization; Escherichia coli/chemistry; Escherichia coli/genetics; Escherichia coli Proteins/biosynthesis; Escherichia coli Proteins/chemistry; Escherichia coli Proteins/genetics; Gene Expression Regulation, Bacterial; Glutamic Acid/chemistry; Glutamic Acid/genetics; Glutamine/chemistry; Glutamine/genetics; Membrane Proteins/chemistry; Membrane Proteins/genetics; Molecular Sequence Data; Periplasmic Binding Proteins/biosynthesis; Periplasmic Binding Proteins/genetics; Protein Structure, Tertiary/genetics; Receptors, Amino Acid/chemistry; Receptors, Amino Acid/genetics; Receptors, Cell Surface/chemistry; Receptors, Cell Surface/genetics; Recombinant Fusion Proteins/chemistry; Recombinant Fusion Proteins/genetics; Serine/chemistry; Serine/genetics; Transcription Factors/biosynthesis; Transcription Factors/genetics
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