Signaling pathways and the cerebral cavernous malformations proteins: lessons from structural biology

Abstract

Cerebral cavernous malformations (CCM) are neurovascular dysplasias that result in mulberry-shaped lesions predominantly located in brain and spinal tissues. Mutations in three genes are associated with CCM. These genes encode for the proteins KRIT1/CCM1 (krev interaction trapped 1/cerebral cavernous malformations 1), cerebral cavernous malformations 2, osmosensing scaffold for MEKK3 (CCM2/malcavernin/OSM), and cerebral cavernous malformations 3/programmed cell death 10 (CCM3/PDCD10). There have been many significant recent advances in our understanding of the structure and function of these proteins, as well as in their roles in cellular signaling. Here, we provide an update on the current knowledge of the structure of the CCM proteins and their functions within cellular signaling, particularly in cellular adhesion complexes and signaling cascades. We go on to discuss subcellular localization of the CCM proteins, the formation and regulation of the CCM complex signaling platform, and current progress towards targeted therapy for CCM disease. Recent structural studies have begun to shed new light on CCM protein function, and we focus here on how these studies have helped inform the current understanding of these roles and how they may aid future studies into both CCM-related biology and disease mechanisms.

Nuclear Localization of Integrin Cytoplasmic Domain-associated Protein-1 (ICAP1) Influences β1 Integrin Activation and Recruits Krev/Interaction Trapped-1 (KRIT1) to the Nucleus

“…KRIT1 is a multidomain, 736-amino acid protein containing an N-terminal Nudix domain, three NPX(Y/F) motifs, an ankyrin repeat domain, and a FERM domain (12). Notably, loss-of-function (typically nonsense) mutations in KRIT1 are associated with cerebral cavernous malformation (CCM), a common dysplasia of the vasculature (13,14).…”

“…CCMs have been reported in up to 0.5% of the population (16) and are strongly associated with hemorrhagic stroke, seizure, epilepsy, and other focal neurological outcomes. CCMs are also caused by loss of function mutations in CCM2 or CCM3 genes (17), and the CCM2 protein can form the hub of a multiprotein KRIT1-CCM2-CCM3 complex: the CCM complex (12,18,19). Loss of KRIT1, CCM2, or CCM3 proteins is therefore directly associated with focal neurological defects, stroke, and vascular abnormalities.…”

Role of Krev Interaction Trapped-1 in Prostacyclin-Induced Protection against Lung Vascular Permeability Induced by Excessive Mechanical Forces and Thrombin Receptor Activating Peptide 6

“…Vascular abnormalities and the high incidence of seizures and hemorrhagic stroke have been described in patients with CCMs with mutations in the KRIT1/ CCM2 genetic locus (44,45) and are associated with weakening of brain microvascular EC junctions and elevation of Rho activity (33). Compromised vascular lumen organization in CCM also suggests a KRIT1 role in the control of the endothelial polarity complex (46).…”

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“…The three proteins implicated in the disease were predicted to be distinct from one another in structure, but their molecular level architecture and many details of their normal function and protein-protein interaction networks were unknown. Therefore, to better understand the signaling processes that are affected by CCM disease it was necessary to address these questions from the ground up, starting at the atomic level [2].…”

“…The three proteins implicated in the disease were predicted to be distinct from one another in structure, but their molecular level architecture and many details of their normal function and protein-protein interaction networks were unknown. Therefore, to better understand the signaling processes that are affected by CCM disease it was necessary to address these questions from the ground up, starting at the atomic level [2].The formation of a 'CCM complex' between KRIT1, CCM2 and CCM3 was previously suggested, but without targeted disruption of the interactions and selective probing of the functional consequences of disruption, the specific role(s) of heterotrimerization have been hard to define. We tackled these questions using a structure-directed approach.…”