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Biochim Biophys Acta. 2014 Sep;1838(9):2313-8. doi: 10.1016/j.bbamem.2014.05.006. Epub 2014 May 17.

Proline localized to the interaction interface can mediate self-association of transmembrane domains.

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Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel; Department of Microbiology and Immunology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel. Electronic address:
Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel; The Mina & Everard Goodman Faculty of Life Sciences, The Nanotechnology Institute, Bar-Ilan University, Ramat Gan 52900, Israel.
Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel.


Assembly of transmembrane domains (TMDs) is a critical step in the function of membrane proteins. In recent years, the role of specific amino acids in TMD-TMD interactions has been better characterized, with more emphasis on polar and aromatic residues. Despite the high abundance of proline residues in TMDs, contribution of proline to TMD-TMD association has not been intensively studied. Here, we evaluated statistically the frequency of appearance, and experimentally the contribution of proline, compared to other hydrophobic amino acids (Gly, Ala, Val, Leu, Ile, and Met), with regard to TMD-TMD self-assembly. Our model system is the assembly motif ((22)QxxS(25)) found previously in TMDs of the Escherichia coli aspartate receptor (Tar-1). Statistically, our data revealed that all different motifs, except PxxS (P/S), have frequencies similar to their theoretical random expectancy within a database of 41916 sequences of TMDs, while PxxS motif is underrepresented. Experimentally, using the ToxR assembly system, the SDS-gel running pattern of biotin-conjugated TMD peptides, and FRET experiments between fluorescence-labeled peptides, we found that only the P/S motif preserves the dimerization ability of wild-type Tar-1 TMD. Although proline is known as a helix breaker in solution, Circular Dichroism spectroscopy revealed that the secondary structure of the P/S and the wild-type peptides are similar. All together, these data suggest that proline can stabilize TM self-assembly when localized to the interaction interface of a transmembrane oligomer. This article is part of a Special Issue entitled: Interfacially Active Peptides and Proteins. Guest Editors: William C. Wimley and Kalina Hristova.


Helix–helix interaction; Peptide membrane interaction; Recognition within the membrane; TM–TM; ToxR; Transmembrane domain

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