9PVG

Co-crystal structure of two CCM2 PTB domains bound to a KRIT1 peptide encompassing NPxF2 and NPxF3

Summary for 9PVG

• Entry DOI: 10.2210/pdb9pvg/pdb
• Descriptor: Malcavernin, Krev interaction trapped protein 1 (2 entities in total)
• Functional Keywords: ptb domain, npxy, npxf, cerebral cavernous malformations, ccm, protein-protein, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 84797.78

Authors

Fisher, O.S.,Boggon, T.J. (deposition date: 2025-08-01, release date: 2026-01-28, Last modification date: 2026-08-12)

Primary citation

Huet-Calderwood, C.,Fisher, O.S.,Das, S.,Su, V.L.,Boggon, T.J.,Calderwood, D.A.
Dual recruitment of two CCM2 molecules to KRIT1 suppresses KLF4 expression.
Nat Commun, 17:-, 2026

PubMed Abstract: Regulated expression of Kruppel like factor (KLF) transcription factors is essential for normal maintenance of endothelial cells, but loss of either K-Rev interaction trapped 1 (KRIT1) or cerebral cavernous malformations 2 (CCM2) proteins results in significant over-expression of KLF4 protein, causing the cerebrovascular disorder, cerebral cavernous malformations. Here, combining knockdown and reconstitution in an endothelial cell line, with co-immunoprecipitation, biophysical analysis of purified proteins, and co-crystallography, we find that to restrain KLF4 expression, two CCM2 proteins must cluster on a single KRIT1, with the PTB domain of each CCM2 protein binding either the second or third NPxF motif within KRIT1. This clustering of two PTB domains to a single peptide reveals a previously unobserved mechanism for PTB domain recruitment to partner proteins. Overall, our data support a model where clustering of two CCM2 molecules to one KRIT1 is required for normal regulation of expression of KLF4 transcription factor.

PubMed: 41688454
DOI: 10.1038/s41467-026-69595-7

Experimental method

X-RAY DIFFRACTION (3 Å)