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Interactions of the Human Calcitonin Fragment 9–32 with Phospholipids: A Monolayer Study

Kerstin Wagner ^* , Nicole Van Mau ^*, Sylvie Boichot , Andrey V. Kajava ^*, Ulrike Krauss , Christian Le Grimellec , Annette Beck-Sickinger  and Frédéric Heitz ^*

^* Centre de Recherches de Biochimie Macromoléculaire-Centre National de la Recherche Scientifique, Formation de Recherche en Evolution 2593, F-34293 Montpellier Cedex, France; Institute of Biochemistry, University of Leipzig, D-04103 Leipzig, Germany; and Nanostructures et Complexes Membranaires, Centre de Biologie Structurale Institut National de la Santé et de la Recherche Medicale U554, F-34090 Montpellier Cedex, France

Correspondence: Address reprint requests to Frédéric Heitz, E-mail: heitz{at}crbm.cnrs-mop.fr; Annette Beck-Sickinger, E-mail: beck-sickinger{at}uni-leipzig.de; or Christian Le Grimellec, E-mail: clg{at}cbs.univ-montp1.fr.

Human calcitonin and its C-terminal fragment 9–32 (hCT(9–32)) administered in a spray translocate into respiratory nasal epithelium with an effect similar to intravenous injection. hCT(9–32) is an efficient carrier to transfer the green fluorescent protein into excised bovine nasal mucosa. To understand the translocation of hCT(9–32) across plasma membranes, we investigated its interactions with phospholipids and its interfacial structure using model lipid monolayers. A combination of physicochemical methods was applied including surface tension measurements on adsorbed and spread monolayers at the air-water interface, Fourier transform infrared, circular dichroism, and atomic force microscopy on Langmuir-Blodgett monolayers. The results disclose that hCT(9–32) preferentially interacts with negatively charged phospholipids and does not insert spontaneously into lipid monolayers. This supports a nonreceptor-mediated endocytic internalization pathway as previously suggested. Structural studies revealed a random coil conformation of hCT(9–32) in solution, transforming to -helices when the peptide is localized at lipid-free or lipid-containing air-water interfaces. Atomic force microscopy studies of monolayers of the peptide alone or mixed with dioleoylphosphatidylcholine revealed that hCT(9–32) forms filaments rolled into spirals. In contrast, when interacting with dioleoylphosphatidylglycerol, hCT(9–32) does not adopt filamentous structures. A molecular model and packing is proposed for the spiral-forming hCT(9–32).