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Structural and Functional Roles of HIV-1 gp41 Pretransmembrane Sequence Segmentation

Asier Sáez-Cirión ^*, José L. R. Arrondo ^*, María J. Gómara ^*, Maier Lorizate ^*, Ibón Iloro ^*, Grigory Melikyan  and José L. Nieva ^*

^* Unidad de Biofísica (CSIC-UPV/EHU) and Departamento de Bioquímica, Universidad del País Vasco, 48080 Bilbao, Spain; and Department of Molecular Biophysics and Physiology, Rush Medical College, Chicago, Illinois 60612 USA

Correspondence: Address reprint requests to Dr. José L. Nieva, Tel.: +34-94-6013353; Fax: +34-94-4643360; E-mail: gbpniesj{at}lg.ehu.es.

The membrane-proximal segment connecting the helical core with the transmembrane anchor of human immunodeficiency virus type 1 gp41 is accessible to broadly neutralizing antibodies and plays a crucial role in fusion activity. New predictive approaches including computation of interfacial affinity and the corresponding hydrophobic moments suggest that this region is functionally segmented into two consecutive subdomains: one amphipathic at the N-terminal side and one fully interfacial at the C-terminus. The N-terminal subdomain would extend -helices from the preceding carboxy-terminal heptad repeat and provide, at the same time, a hydrophobic-at-interface surface. Experiments were performed to compare a wild-type representing pretransmembrane peptide with a nonamphipathic defective sequence, which otherwise conserved interfacial hydrophobicity at the carboxy-subdomain. Results confirmed that both penetrated equally well into lipid monolayers and both were able to partition into membrane interfaces. However only the functional sequence: 1), adopted helical structures in solution and in membranes; 2), formed homo-oligomers in solution and membranes; and 3), inhibited gp41-induced cell-cell fusion. These data support two roles for gp41 aromatic-rich pretransmembrane sequence: 1), oligomerization of gp41; and 2), immersion into the viral membrane interface. Accessibility to membrane interfaces and subsequent adoption of the low-energy structure may augment helical bundle formation and perhaps be related to a concomitant loss of immunoreactivity. These results may have implications in the development of HIV-1 fusion inhibitors and vaccines.

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