TCB Publications - Abstract

Boon Chong Goh, Huixing Wu, Michael J. Rynkiewicz, Klaus Schulten, Barbara A. Seaton, and Francis X. McCormack. Elucidation of lipid binding sites on lung surfactant protein A using X-ray crystallography, mutagenesis and molecular dynamics simulations. Biochemistry, 55:3692-3701, 2016.

GOH2016 Surfactant protein A (SP-A) is a collagenous C-type lectin (collectin) that is critical for pulmonary defense against inhaled microorganisms. Bifunctional avidity of SP-A for pathogen associated molecular patterns (PAMPs) such as lipid A and for dipalmitoylphosphatidylcholine (DPPC), the major component of surfactant membranes lining the air liquid interface of the lung, ensures that the protein is poised for first line interactions with inhaled pathogens. To better understand the motifs that are required for interactions with microbes and surfactant structures, we explored the role of the tyrosine- rich binding surface on the carbohydrate recognition domain of SP-A in the interaction with DPPC and lipid A using crystallography, site-directed mutagenesis, and molecular dynamics simulations. Critical binding features for DPPC binding include a three-walled tyrosine cage that binds the choline head group through cation-$\pi$ interactions and a positively charged cluster that binds the phosphoryl group. This basic cluster is also critical for binding of lipid A, a bacterial PAMP and target for SP-A. Molecular dynamics simulations further predict that SP-A binds lipid A more tightly than DPPC. These results suggest that the differential binding properties of SP-A favor transfer of the protein from surfactant DPPC to pathogen membranes containing appropriate lipid PAMPs to effect key host defense functions.


Download Full Text

The manuscripts available on our site are provided for your personal use only and may not be retransmitted or redistributed without written permissions from the paper's publisher and author. You may not upload any of this site's material to any public server, on-line service, network, or bulletin board without prior written permission from the publisher and author. You may not make copies for any commercial purpose. Reproduction or storage of materials retrieved from this web site is subject to the U.S. Copyright Act of 1976, Title 17 U.S.C.

Download full text: Request a Copy, Journal