Structural and functional analysis of human liver-expressed antimicrobial peptide 2

Henriques, Sónia Troeira; Tan, Chia Chia; Craik, David J.; Clark, Richard J.

http://hdl.handle.net/10451/7614

Use this identifier to reference this record.

Name:	Description:	Size:	Format:
Artigo.pdf		921.96 KB	Adobe PDF	Download

Send Feedback

Authors

Henriques, Sónia Troeira

Tan, Chia Chia

Craik, David J.

Clark, Richard J.

Abstract(s)

Human liver-expressed antimicrobial peptide 2 (LEAP-2) is a cationic antimicrobial peptide (CAMP) believed to have a protective role against bacterial infection. Little is known about the structure–activity relationships of LEAP-2 or its mechanism of ction. In this study we describe the structure of LEAP-2, analyze its interaction with model membranes, and relate them to the antimicrobial activity of the peptide. The structure of LEAP-2, determined by NMR spectroscopy, reveals a compact central core with disorder at the N and C termini. The core comprises a β-hairpin and a 3ıо- helix that are braced by disulfide bonds between Cys17–28 and Cys23–33 and further stabilized by a network of hydrogen bonds. Membrane-affinity studies show that LEAP-2 membrane binding is governed by electrostatic attractions, which are sensitive to ionic strength. Truncation studies show that the C-terminal region of LEAP-2 is irrelevant for membrane binding, whereas the N-terminal (hydrophobic domain) and core regions (cationic domain) are essential. Bacterial-growth-inhibition assays reveal that the antimicrobial activity of LEAP-2 correlates with membrane affinity. Interestingly, the native and reduced forms of LEAP-2 have similar membrane affinity and antimicrobial activities ; this suggests that disulfide bonds are not essential for the bactericidal activity. This study reveals that LEAP-2 has a novel fold for a CAMP and suggests that although LEAP-2 exhibits antimicrobial activity under low-salt conditions, there is likely to be another physiological role for the peptide.