The Protein That Refuses to Have One Shape
Textbooks promised one sequence, one structure. Lymphotactin never read them.
By The Editors/November 7, 2026/1 min read
Christian Anfinsen won a share of the 1972 Nobel Prize in Chemistry for an idea that became the working assumption of a field: a protein's amino acid sequence determines its native shape. Unfold the protein gently, let it recover, and it finds the same structure again.
Lymphotactin, a small human signaling protein also known as XCL1, keeps two. In one form it adopts the classic chemokine fold and binds its receptor. In the other it rearranges into an entirely different all-beta structure and binds glycosaminoglycans, the sugar chains that decorate cell surfaces. Under near-physiological conditions, the two forms exist in equilibrium. Brian Volkman's group described the interconversion in 2008.
Not a lone exception
Other proteins do it too. The bacterial transcription factor RfaH has a domain that flips from an alpha-helical hairpin to a beta barrel, changing its job in the process. KaiB, part of the cyanobacterial circadian clock, switches folds as part of how the clock keeps time.
Researchers call these metamorphic proteins, and they are awkward for anyone building tools on the assumption that a sequence maps to a single answer.
Anfinsen's principle survives this. Metamorphic proteins still obey thermodynamics. Their energy landscapes simply have two deep valleys where we expected one. What changes is the casual version of the rule, the one that treats structure as a fixed property a protein has. For a few proteins, at least, structure is something they do.
Sources
- Tuinstra RL et al. Interconversion between two unrelated protein folds in the lymphotactin native state. PNAS, 2008.
- Burmann BM et al. An α helix to β barrel domain switch transforms the transcription factor RfaH into a translation factor. Cell, 2012.
- Chang YG et al. A protein fold switch joins the circadian oscillator to clock output in cyanobacteria. Science, 2015.
