Author
Listed:
- Frans J Walther
- Alan J Waring
- Jose M Hernandez-Juviel
- Larry M Gordon
- Zhengdong Wang
- Chun-Ling Jung
- Piotr Ruchala
- Andrew P Clark
- Wesley M Smith
- Shantanu Sharma
- Robert H Notter
Abstract
Background: Surfactant protein B (SP-B; 79 residues) belongs to the saposin protein superfamily, and plays functional roles in lung surfactant. The disulfide cross-linked, N- and C-terminal domains of SP-B have been theoretically predicted to fold as charged, amphipathic helices, suggesting their participation in surfactant activities. Earlier structural studies with Mini-B, a disulfide-linked construct based on the N- and C-terminal regions of SP-B (i.e., ∼residues 8–25 and 63–78), confirmed that these neighboring domains are helical; moreover, Mini-B retains critical in vitro and in vivo surfactant functions of the native protein. Here, we perform similar analyses on a Super Mini-B construct that has native SP-B residues (1–7) attached to the N-terminus of Mini-B, to test whether the N-terminal sequence is also involved in surfactant activity. Methodology/Results: FTIR spectra of Mini-B and Super Mini-B in either lipids or lipid-mimics indicated that these peptides share similar conformations, with primary α-helix and secondary β-sheet and loop-turns. Gel electrophoresis demonstrated that Super Mini-B was dimeric in SDS detergent-polyacrylamide, while Mini-B was monomeric. Surface plasmon resonance (SPR), predictive aggregation algorithms, and molecular dynamics (MD) and docking simulations further suggested a preliminary model for dimeric Super Mini-B, in which monomers self-associate to form a dimer peptide with a “saposin-like” fold. Similar to native SP-B, both Mini-B and Super Mini-B exhibit in vitro activity with spread films showing near-zero minimum surface tension during cycling using captive bubble surfactometry. In vivo, Super Mini-B demonstrates oxygenation and dynamic compliance that are greater than Mini-B and compare favorably to full-length SP-B. Conclusion: Super Mini-B shows enhanced surfactant activity, probably due to the self-assembly of monomer peptide into dimer Super Mini-B that mimics the functions and putative structure of native SP-B.
Suggested Citation
Frans J Walther & Alan J Waring & Jose M Hernandez-Juviel & Larry M Gordon & Zhengdong Wang & Chun-Ling Jung & Piotr Ruchala & Andrew P Clark & Wesley M Smith & Shantanu Sharma & Robert H Notter, 2010.
"Critical Structural and Functional Roles for the N-Terminal Insertion Sequence in Surfactant Protein B Analogs,"
PLOS ONE, Public Library of Science, vol. 5(1), pages 1-20, January.
Handle:
RePEc:plo:pone00:0008672
DOI: 10.1371/journal.pone.0008672
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