Critical Structural and Functional Roles for the N-terminal Insertion Sequence in Surfactant Protein B Analogs

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2010 Jan 20

PMID 20084172

Citations 31

Authors

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

Affiliations

Soon will be listed here.

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., approximately 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 alpha-helix and secondary beta-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.

Citing Articles

Structure and Function of Canine SP-C Mimic Proteins in Synthetic Surfactant Lipid Dispersions.

Walther F, Waring A Biomedicines. 2024; 12(1).

PMID: 38255268 PMC: 10813813. DOI: 10.3390/biomedicines12010163.

Lung Surfactant Protein B Peptide Mimics Interact with the Human ACE2 Receptor.

Waring A, Jung G, Sharma S, Walther F Int J Mol Sci. 2023; 24(13).

PMID: 37446012 PMC: 10341807. DOI: 10.3390/ijms241310837.

Emulation of the structure of the Saposin protein fold by a lung surfactant peptide construct of surfactant Protein B.

Waring A, Whitelegge J, Sharma S, Gordon L, Walther F PLoS One. 2022; 17(11):e0276787.

PMID: 36327300 PMC: 9632872. DOI: 10.1371/journal.pone.0276787.

Aerosol Delivery of Lung Surfactant and Nasal CPAP in the Treatment of Neonatal Respiratory Distress Syndrome.

Walther F, Waring A Front Pediatr. 2022; 10:923010.

PMID: 35783301 PMC: 9240419. DOI: 10.3389/fped.2022.923010.

Efficacy, dose-response, and aerosol delivery of dry powder synthetic lung surfactant treatment in surfactant-deficient rabbits and premature lambs.

Walther F, Waring A, Otieno M, DiBlasi R Respir Res. 2022; 23(1):78.

PMID: 35379243 PMC: 8978426. DOI: 10.1186/s12931-022-02007-8.

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