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Transmembrane Domain Oligomerization Propensity determined by ToxR Assay
Published on: May 26, 2011
Structural basis for dimerization of the BNIP3 transmembrane domain
Endah S Sulistijo1, Kevin R Mackenzie
1Department of Biochemistry and Cell Biology, Rice University, 6100 Main Street, Houston, Texas 77005, USA.
Biochemistry
|May 7, 2009
Summary
The BNIP3 transmembrane domain forms a symmetric dimer stabilized by His-Ser hydrogen bonds and steric interactions. Lipid environment influences structure, with specific residues critical for dimerization.
Area of Science:
- Biochemistry
- Structural Biology
- Membrane Proteins
Background:
- Mutagenesis studies suggested His 173 and Ser 172 are critical for BNIP3 transmembrane domain dimerization via hydrogen bonding.
- Previous structural analyses indicated these residues adopt multiple conformations, questioning the consistent hydrogen bond formation.
Purpose of the Study:
- To elucidate the structural basis of BNIP3 transmembrane domain dimerization.
- To investigate the role of phospholipids in stabilizing the dimer structure.
- To determine the precise interactions, including hydrogen bonding and steric effects, that govern dimerization.
Main Methods:
- Nuclear Magnetic Resonance (NMR) spectroscopy in dodecylphosphocholine (DPC) micelles.
- Lipid titration to optimize peptide reconstitution.
- Structural determination of the BNIP3 transmembrane domain dimer.
- Computational modeling of mutagenesis data.
Main Results:
- Reconstitution in DPC micelles with lipid titration yielded a well-defined symmetric dimer structure.
- The structure revealed critical intermonomer hydrogen bonding between His 173 and Ser 172 side chains.
- Small residues (Ala 176, Gly 180, Gly 184) facilitate helix proximity, while bulky residues (Ile 177, Ile 181) engage in favorable packing.
- Modeling confirmed that mutations disrupting His-Ser hydrogen bonds or causing steric clashes are deleterious to dimerization.
- Non-interfacial substitutions generally had no effect, except for Ile 183, suggesting potential peptide-lipid interactions.
Conclusions:
- The BNIP3 transmembrane domain dimer is stabilized by a combination of specific hydrogen bonds (His 173-Ser 172) and steric interactions.
- Phospholipids play a crucial role in modulating the structure and enabling the formation of a stable dimer.
- Sequence-dependent dimerization is governed by both direct interfacial contacts and potentially interactions with the lipid environment.
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