Crystal Structure of CCM3, a Cerebral Cavernous Malformation Protein Critical for Vascular Integrity

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2010 May 22

PMID 20489202

Citations 48

Authors

Xiaofeng Li

Rong Zhang

Haifeng Zhang

Yun He

Weidong Ji

Wang Min

Titus J Boggon

Affiliations

Soon will be listed here.

Abstract

CCM3 mutations are associated with cerebral cavernous malformation (CCM), a disease affecting 0.1-0.5% of the human population. CCM3 (PDCD10, TFAR15) is thought to form a CCM complex with CCM1 and CCM2; however, the molecular basis for these interactions is not known. We have determined the 2.5 A crystal structure of CCM3. This structure shows an all alpha-helical protein containing two domains, an N-terminal dimerization domain with a fold not previously observed, and a C-terminal focal adhesion targeting (FAT)-homology domain. We show that CCM3 binds CCM2 via this FAT-homology domain and that mutation of a highly conserved FAK-like hydrophobic pocket (HP1) abrogates CCM3-CCM2 interaction. This CCM3 FAT-homology domain also interacts with paxillin LD motifs using the same surface, and partial CCM3 co-localization with paxillin in cells is lost on HP1 mutation. Disease-related CCM3 truncations affect the FAT-homology domain suggesting a role for the FAT-homology domain in the etiology of CCM.

Citing Articles

Comprehensive CCM3 Mutational Analysis in Two Patients with Syndromic Cerebral Cavernous Malformation.

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The Dual Role of PDCD10 in Cancers: A Promising Therapeutic Target.

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Is Location Everything? Regulation of the Endothelial CCM Signaling Complex.

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Endothelial Cell-Pericyte Interactions in the Pathogenesis of Cerebral Cavernous Malformations (CCMs).

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