Observation of signal transduction in three-dimensional domain swapping

Joost W.H. Schymkowitz, Frederic Rousseau, Hannah R. Wilkinson, Assaf Friedler, Laura S. Itzhaki*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

50 Scopus citations


p13suc1 (suc1) has two native states, a monomer and a domain-swapped dimer. The structure of each subunit in the dimer is identical to that of the monomer, except for the hinge loop that connects the exchanging domains. Here we find that single point mutations at sites throughout the protein and ligand binding both shift the position of the equilibrium between monomer and dimer. The hinge loop was shown previously to act as a loaded molecular spring that releases tension present in the monomer by adopting an alternative conformation in the dimer. The results here indicate that the release of strain propagates throughout the entire protein and alters the energetics of regions remote from the hinge. Our data illustrate how the signal conferred by the conformational change of a protein loop, elicited by domain swapping, ligand binding or mutation, can be sensed by a distant active site. This work highlights the potential role of strained loops in proteins: The energy they store can be used for both signal transduction and allostery, and they could steer the evolution of protein function. Finally, a structural mechanism for the role of suc1 as an adapter molecule is proposed.

Original languageAmerican English
Pages (from-to)888-892
Number of pages5
JournalNature Structural Biology
Issue number10
StatePublished - 2001
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by the MRC of the UK. L.S.I. was supported by a Career Development Award from the MRC of the UK. J.W.H.S. and F.R. were supported by Marie Curie Training and Mobility of Research Fellowships from the E.C. A.F. is supported by a Human Frontier Science Program long term fellowship. We thank A.R. Fersht and J. Clarke for useful discussions and S. Kazmirski for help with analyzing the crystal structures.


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