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Cell-Cell Interaction: A FERM Connection

SBKB [doi:10.1038/sbkb.2012.128]
Featured Article - March 2013
Short description: The structure of a KRIT1–HEG1 complex reveals a new binding mechanism for FERM domains.

Ribbon diagram of the KRIT1 FERM domain bound to the HEG1 cytoplasmic tail (PDB 3U7D). HEG1, shown in yellow, binds in a hydrophobic pocket at the F1 and F3 interface. Figure courtesy of Mark Ginsberg.

The endothelial cells of the vasculature are held together via cell junctions, in which transmembrane proteins form a physical link between neighboring cells and intracellular proteins. One such interaction occurs between the transmembrane protein HEG1 and the intracellular protein KRIT1, both part of a complex that stabilizes endothelial cell junctions. Defects in components of this complex cause disruption of endothelial cell junctions, resulting in vascular lesions in the brain and retina. In humans, this results in a familial form of cerebral cavernous malformation, a condition that increases the risk of seizures, hemorrhagic stroke and other neurological defects.

KRIT1 contains a FERM domain, a cloverleaf-shaped domain that mediates protein-protein interactions. The F3 subdomain of KRIT1's FERM domain has been predicted to contain a phosphotyrosine-binding (PTB) domain. Since the C-terminus of HEG1 contains a consensus motif known to interact with PTB domains, the binding mode between these two proteins seemed clear.

However, isothermal titration calorimetry results suggested that the PTB domain-binding sequence of HEG1 was not involved in KRIT1 interaction. This led Ginsberg and colleagues, as part of the CELLMAT PSI:Biology partnership, to determine the crystal structure of the FERM domain of KRIT1 in complex with a peptide corresponding to the last 26 residues of HEG1 (PDB 3U7D). The structure revealed a new type of interaction with a FERM domain, in which HEG1 interacts with a hydrophobic groove between the F1 and F3 subdomains of KRIT1. This interaction leaves the PTB domain of KRIT1 available to engage in autoinhibitory interactions with the N-terminus of KRIT1 or with other binding partners.

The authors confirmed the biological importance of this interaction by mutating residues in KRIT1 that disrupted its interaction with HEG1, without affecting interactions with other binding partners. Disruption of the KRIT1–HEG1 interaction abrogated localization of KRIT1 to cell-cell junctions and impaired cardiovascular development in zebrafish.

The structure of the KRIT1–HEG1 complex provides evidence for the role of HEG1 in localizing KRIT1 to cell-cell junctions and reveals a previously unidentified binding mode for FERM domains.

Jennifer Cable


  1. A.R. Gingras, J.J. Liu & M.H. Ginsberg. Structural basis of the junctional anchorage of the cerebral cavernous malformations complex.
    J. Cell Biol. 199, 39-48 (2012). doi:10.1083/jcb.201205109

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