Despite a conserved cystine knot motif, different cyclotides have different membrane binding modes
Conan K Wang1, Michelle L Colgrave, David C Ireland
1University of Queensland, Institute for Molecular Bioscience, Brisbane, Queensland, Australia.
Biophysical Journal
|September 2, 2009
Summary
Cyclotides, stable plant defense proteins, interact with membranes. Their distinct hydrophobic patches dictate unique binding orientations, offering insights into therapeutic potential.
Area of Science:
- Biochemistry
- Structural Biology
- Pharmacology
Background:
- Cyclotides are plant-derived cyclic peptides with notable stability and bioactivity.
- Their therapeutic potential is linked to interactions with biological membranes.
- Understanding cyclotide structure-activity relationships is crucial for drug development.
Purpose of the Study:
- To elucidate the structural basis of biological activity in two major cyclotide subfamilies.
- To determine the membrane-bound conformation and orientation of kalata B2 (Möbius) and cycloviolacin O2 (bracelet) cyclotides.
Main Methods:
- Nuclear Magnetic Resonance (NMR) spectroscopy was employed to study cyclotides bound to dodecylphosphocholine micelles.
- Paramagnetic relaxation probes (doxylstearates) and Mn ions were used to assess cyclotide location and orientation.
- Langmuir isotherm analysis quantified binding affinities.
Main Results:
- Both kalata B2 and cycloviolacin O2 bind to micelle surfaces with moderate affinity.
- Distinct binding orientations were observed for the Möbius and bracelet cyclotide subfamilies.
- Cycloviolacin O2 features a beta-hairpin in loop 5 and a helical turn in loop 3, with a hydrophobic patch across loops 2 and 3.
- Kalata B2 exhibits a different hydrophobic patch distribution, primarily involving loops 2 and 5.
Conclusions:
- The differential positioning of hydrophobic patches explains the distinct membrane binding orientations of cyclotide subfamilies.
- This structural insight is key to understanding the diverse bioactivities and therapeutic potential of cyclotides.
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