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J. Biol. Chem., Vol. 280, Issue 29, 27449-27457, July 22, 2005

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The Identification of a Minimal Dimerization Motif QXXS That Enables Homo- and Hetero-association of Transmembrane Helices in Vivo^*

Neta Sal-Man, Doron Gerber, and Yechiel Shai

From the Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel

Assembly of transmembrane (TM) domains is a critical step in the function of membrane proteins, and therefore, determining the amino acid motifs that mediate this process is important. Studies along this line have shown that the GXXXG motif is involved in TM assembly. In this study we characterized the minimal dimerization motif in the bacterial Tar-1 homodimer TM domain, which does not contain a GXXXG sequence. We found that a short polar motif QXXS is sufficient to induce stable TM-TM interactions. Statistical analysis revealed that this motif appears to be significantly over-represented in a bacterial TM data base compared with its theoretical expectancy, suggesting a general role for this motif in TM assembly. A truncated short TM peptide (9 residues) that contains the QXXS motif interacted slightly with the wild-type Tar-1. However, the same short TM peptide regained wild-type-like activity when conjugated to an octanoyl aliphatic moiety. Biophysical studies indicated that this modification compensated for the missing hydrophobicity, stabilized -helical structure, and enabled insertion of the peptide into the membrane core. These findings serve as direct evidence that even a short peptide containing a minimal recognition motif is sufficient to inhibit the proper assembly of TM domains. Interestingly, electron microscopy revealed that above the critical micellar concentration, the TM lipopeptide forms a network of nanofibers, which can serve for the slow release of the active lipopeptide.

Received for publication, March 21, 2005 , and in revised form, May 11, 2005.

^* This work was supported by The Dr. Josef Cohn Minerva Center for Biomembrane Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Harold S. and Harriet B. Brady Professorial Chair in Cancer Research. To whom correspondence should be addressed: Dept. of Biological Chemistry, The Weizmann Institute of Science, Rehovot, 76100 Israel. Tel.: 972-8-9342711; Fax: 972-8-9344112; E-mail: Yechiel.Shai{at}weizmann.ac.il.

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