De novo design of a transmembrane Zn2+-transporting four-helix bundle
By N. Joh, Tuo Wang, Manasi P. Bhate, Rudresh Acharya, Yibing Wu, M. Grabe, M. Hong, Gevorg Grigoryan, William F. DeGrado. 2014
291 citations recorded by the source corpus.
The design of functional membrane proteins from first principles represents a grand challenge in chemistry and structural biology. Here, we report the design of a membrane-spanning, four-helical bundle that transports first-row transition metal ions Zn2+ and Co2+, but not Ca2+, across membranes. The conduction path was designed to contain two di-metal binding sites that bind with negative cooperativity. X-ray crystallography and solid-state and solution nuclear magnetic resonance indicate that the overall helical bundle is formed from two tightly interacting pairs of helices, which form individual domains that interact weakly along a more dynamic interface. Vesicle flux experiments show that as Zn2+ ions diffuse down their concentration gradients, protons are antiported. These experiments illustrate the feasibility of designing membrane proteins with predefined structural and dynamic properties. Computational design yields a transmembrane protein that selectively transports zinc cations. [Also see Perspective by Lupas] Building transmembrane zinc transporters The ability to design proteins gives insight into the relation between a protein's fold and its function and also provides a path to custom proteins for bioengineering applications. Impressive strides have been made in the design of soluble proteins, but designing membrane proteins remains a challenge. Joh et al. achieve a milestone by designing a transmembrane Zn2+ transporter (see the Perspective by Lupas). The protein comprises four helices: Two tightly interacting pairs form a weaker interface that facilitates the transport of Zn2+ with concomitant reverse transport of protons. Science, this issue p. 1520; see also p. 1455
Subfields: Molecular Biology, Spectroscopy
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In Molecular Biology
- Xingjie Pan
- Christopher W. Wood
- Tanja Kortemme
- Gevorg Grigoryan
- Zak Costello
- Bruno E. Correia
- Che Yang
- S. Rosset
In Spectroscopy
- Bruno E. Correia
- Benjamin T. Porebski
- Derek N. Woolfson
- Ashley M. Buckle
- Tanja Kortemme
- John Ingraham
- Xingjie Pan
- Freyr Sverrisson
Citations in the corpus
- Recent advances in de novo protein design: Principles, methods, and applications (2021, methodology): “Membrane-spanning peptides that self-assemble into helical bundles were designed to perform functions such as cofactor binding (146) and ion transport (24).”
- Consensus protein design (2016, methodology): “Directed evolution and informatics-based rational design are transforming the field of protein engineering (Arnold and Volkov, 1999; Jiang et al., 2008; Lutz, 2010; Brustad and Arnold, 2011; Bornscheuer et al., 2012; Joh et al., 2014; Woolfson et al., 2015).”
- 2018). CCBuilder 2.0: Powerful and accessible coiled-coil modeling (2017, background): “4,9,10,14,15 Coiled coils account for between 3% and 5% of all protein-encoding DNA.”