Structural model for an AxxxG‐mediated dimer of surfactant‐associated protein C

Abstract

The pulmonary surfactant prevents alveolar collapse and is required for normal pulmonary function. One of the important components of the surfactant besides phospholipids is surfactant‐associated protein C (SP‐C). SP‐C shows complex oligomerization behavior and a transition to β‐amyloid‐like fibril structures, which are not yet fully understood. Besides this nonspecific oligomerization, MS and chemical cross‐linking data combined with CD spectra provide evidence of a specific, mainly α‐helical, dimer at low to neutral pH. Furthermore, resistance to CNBr cleavage and dual NMR resonances of porcine and human recombinant SP‐C with Met32 replaced by isoleucine point to a dimerization site located at the C‐terminus of the hydrophobic α‐helix of SP‐C, where a strictly conserved heptapeptide sequence is found. Computational docking of two SP‐C helices, described here, reveals a dimer with a helix–helix interface that strikingly resembles that of glycophorin A and is mediated by an AxxxG motif similar to the experimentally determined GxxxG pattern of glycophorin A. It is highly likely that mature SP‐C adopts such a dimeric structure in the lamellar bilayer systems found in the surfactant. Dimerization has been shown in previous studies to have a role in sorting and trafficking of SP‐C and may also be important to the surfactant function of this protein.

Assignment of oriented sample NMR resonances from a three transmembrane helix protein

“…These motifs can also be seen in the primary sequence in Fig. 2a and are known to provide surfaces for close helix-helix association [56–60] which may cause deviations from ideal helix geometry. Overall, the wave analysis indicates a well-fitting model with constant tilt and rotation angles for all three helices.…”

Oligomerization Domain of the Multidrug Resistance–Associated Transporter ABCG2 and Its Dominant Inhibitory Activity

“…Several other motifs, such as AXXXA, AXXXG, GXXXXXXG, and QXXS, have been suggested to involve interactions between membrane proteins (28,30,31). Examination of the sequence of the domain containing TM5-loop-TM6 of human ABCG2 revealed that they contain only the QXXS motif (Q 569 YFS) in the loop linking TM5 and TM6.…”

Surfactant protein C peptides with salt-bridges (“ion-locks”) promote high surfactant activities by mimicking theα-helix and membrane topography of the native protein

“…1). Extensive 2D-NMR analyses (Luy et al, 2004; Kairys, Gilson & Luy, 2004) indicated that freshly prepared recombinant SP-C in chloroform-methanol is a mixture of monomers and dimers, with a α -helical conformation (residues Phe-5 to Leu-34) that largely overlaps that of porcine SP-C (Johansson et al, 1994). Non-palmitoylated rSP-C shares key metastable characteristics of native porcine SP-C when suspended in chloroform-methanol for several days, such as the conversion of α -helical conformers to insoluble β -sheet multimers (Luy et al, 2004).…”