Technical Highlight - February 2011
Short description: X-ray crystallography of protein complex resolves a controversy regarding domain interactions.
Tumor suppressors regulate a variety of processes in cells in order to restrain cancer progression and metastasis. The adhesion molecule tumor suppressor in lung cancer 1 (TSLC1) shows lost or diminished expression in many metastatic tumors. Through the 4.1 binding motif in its cytoplasmic tail (a hallmark of the protein 4.1 family), TSLC1 interacts with the FERM domain–containing tumor suppressor DAL-1, which controls cell adhesion. However, the significance and molecular details of this interaction are still not clear.
To examine this interaction, Hallberg and colleagues chose an X-ray crystallography approach and have uncovered the basis for the interaction between DAL-1 and TSLC1, providing the first crystal structure of 4.1 superfamily members in complex. The structure shows a peptide derived from TSLC1 binding in a conserved hydrophobic pocket in the C-lobe of the trilobed DAL-1 FERM domain. The overall structure of DAL-1 is not altered by the binding of TSLC1, but local conformational changes stabilize the interaction. These structural insights would be unavailable if either protein was studied individually, thus underscoring the utility of examining crystal structures of protein complexes.
Surface plasmon resonance analysis of TSLC1 binding to DAL-1 revealed both fast and slow reactions, likely representing initial binding and the resulting conformational changes, respectively. The TSLC1–DAL-1 structure has features similar to those due to interactions in other FERM domain–containing proteins and helps to resolve earlier controversy over domain interactions in 4.1 superfamily members. Although the full significance of interactions in FERM domain–containing proteins for tumor progression remains to be revealed, the model provided by this cocrystal will be integral to efforts to understand how tumor cells escape their local environment.
R.D. Busam et al. Structural basis of tumor suppressor in lung cancer 1 (TSLC1) binding to differentially expressed in adenocarcinoma of the lung (DAL-1/4.1B).
J Biol Chem. Published online 3 December 2010. doi: 10.1074/jbc.M110.174011