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TLNRD1 is a CCM complex component and regulates endothelial barrier integrity

Ball, Neil J. and Ghimire, Sujan and Follain, Gautier and Pajari, Ada O and Vaitkevicˇiu ̄te ̇, Monika and Cowell, Alana R and Berki, Bence and Ivaska, Johanna and Paatero, Ilkka and Goult, Benjamin T and Jacquemet, Guillaume (2023) TLNRD1 is a CCM complex component and regulates endothelial barrier integrity. [Preprint] (doi:10.1101/2023.09.29.559344) (KAR id:103069)

Abstract

We previously identified talin rod domain-containing protein 1 (TLNRD1) as a potent actin-bundling protein in vitro. Here, we report that TLNRD1 is primarily expressed in the vasculature in vivo and that its depletion leads to vascular abnormalities in vivo and loss of barrier integrity in cultured endothelial cells. We demonstrate that TLNRD1 is a component of the cerebral cavernous malformations (CCM) complex through its direct, high-affinity interaction with CCM2. Modeling and functional testing of TLNRD1 and CCM2 mutants reveal that their interaction is mediated by a hydrophobic C-terminal helix in CCM2 that attaches to a hydrophobic groove on the 4-helix domain of TLNRD1. Disruption of this binding interface leads to CCM2 and TLNRD1 accumulation in the nucleus and actin fibers. Notably, a CCM2 pathogenic mutation linked to vascular dementia in patients maps to the interface and disrupts the interaction. Our findings indicate that CCM2 controls TLNRD1 localization to the cytoplasm and inhibits its actin-bundling activity. Based on these results, we propose a new pathway by which the CCM complex modulates the actin cytoskeleton and vascular integrity by controlling TLNRD1 bundling activity.

Item Type: Preprint
DOI/Identification number: 10.1101/2023.09.29.559344
Refereed: No
Name of pre-print platform: bioRxiv
Uncontrolled keywords: TLNRD1, CCM complex, vasculature disorder, CCM2
Subjects: Q Science > QH Natural history > QH581.2 Cell Biology
Divisions: Divisions > Division of Natural Sciences > Biosciences
Funders: Cancer Research UK (https://ror.org/054225q67)
Depositing User: Ben Goult
Date Deposited: 29 Sep 2023 22:56 UTC
Last Modified: 02 Oct 2023 10:32 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/103069 (The current URI for this page, for reference purposes)

University of Kent Author Information

Ball, Neil J..

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CReDIT Contributor Roles:

Goult, Benjamin T.

Creator's ORCID: https://orcid.org/0000-0002-3438-2807
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