Cholesterol reduces pardaxin's dynamics-a barrel-stave mechanism of membrane disruption investigated by solid-state NMR.
While high-resolution 3D structures reveal the locations of all atoms in a molecule, it is the dynamics that correlates the structure with the function of a biological molecule. The complete characterization of dynamics of a membrane protein is in general complex. In this study, we report the influence of dynamics on the channel-forming function of pardaxin using chemical shifts and dipolar couplings measured from 2D broadband-PISEMA experiments on mechanically aligned phospholipids bilayers. Pardaxin is a 33-residue antimicrobial peptide originally isolated from the Red Sea Moses sole, Pardachirus marmoratus, which functions via either a carpet-type or barrel-stave mechanism depending on the membrane composition. Our results reveal that the presence of cholesterol significantly reduces the backbone motion and the tilt angle of the C-terminal amphipathic helix of pardaxin. In addition, a correlation between the dynamics-induced heterogeneity in the tilt of the C-terminal helix and the membrane disrupting activity of pardaxin by the barrel-stave mechanism is established. This correlation is in excellent agreement with the absence of hemolytic activity for the derivatives of pardaxin. These results explain the role of cholesterol in the selectivity of the broad-spectrum of antimicrobial activities of pardaxin.
Ramamoorthy
Ayyalusamy
A
Biophysics and Department of Chemistry, University of Michigan, Ann Arbor, MI 48109-1055, USA. ramamoor@umich.edu
Lee
Dong-Kuk
DK
Narasimhaswamy
Tennaru
T
Nanga
Ravi P R
RP
D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry*; D002784:Cholesterol / Q000737:chemistry*; D029941:Fish Proteins / Q000737:chemistry*; D005397:Fish Venoms / Q000737:chemistry*; D005399:Fishes; D008051:Lipid Bilayers / Q000737:chemistry*; D019906:Nuclear Magnetic Resonance, Biomolecular; D010743:Phospholipids / Q000737:chemistry*; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship
D000890:Anti-Infective Agents; D029941:Fish Proteins; D005397:Fish Venoms; D008051:Lipid Bilayers; D010743:Phospholipids; C017603:pardaxin; D002784:Cholesterol