Katherine Shelley presented de novo designed protein domains that repeatedly capture and release a peptide in response to light
Katherine Shelley presented de novo designed protein domains that repeatedly capture and release a peptide in response to light
On July 24, Katherine Shelley from David Baker’s laboratory described protein “hinges” that can be switched with ultraviolet and blue light during a Foresight seminar. In the recording published on July 27, she demonstrated the full cycle: light causes a domain to capture a peptide, release it, and repeat the process.
A protein binds its partners through its shape. In 2023, Baker’s team designed protein hinges from scratch with two predetermined conformations. A peptide partner shifted each hinge from the closed state to the open state. The authors used several experimental methods to verify the structures of both conformations and the transition between them.
Shelley’s team added azobenzene to this hinge. Azobenzene is a small molecule that changes its geometry when exposed to light. It attaches to two sites on the protein. Ultraviolet light bends the azobenzene and brings these sites closer together, while blue light returns the molecule to its extended form. The protein responds to this change in distance by adopting a different three-dimensional conformation.
In Shelley’s presentation, seven of eight variants changed their peptide binding after exposure to ultraviolet light. For one variant, the team demonstrated three consecutive cycles: ultraviolet light increased binding, and blue light released the peptide.
Light changes the distance between sites within the protein, and the resulting protein conformation changes its interaction with the peptide. Protein shape therefore becomes a functional part of the mechanism. Fluorescence sensors on the protein independently confirmed the conformational change, while repeated binding cycles confirmed that the mechanism performed the intended action. The positions of the azobenzene attachment sites and the strength of binding to the partner affect how the cycle proceeds. In three variants, switching ten times between ultraviolet and blue light preserved this behavior.
The team has already used these domains to bind and release the BIM-BH3 peptide cyclically, control protein attachment to a surface, and alter hydrogel properties. In the description of the Foresight seminar, Shelley says that the domains can be connected to other proteins. As a next step, she proposes combining elements with different response times so that one protein component passes the action to another. She suggests beginning with protein “walkers” that move along a fiber.