CCM3/PDCD10 Heterodimerizes with Germinal Center Kinase III (GCKIII) Proteins Using a Mechanism Analogous to CCM3 Homodimerization

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2011 May 13

PMID 21561863

Citations 41

Authors

Derek F Ceccarelli

Rob C Laister

Vikram Khipple Mulligan

Michelle J Kean

Marilyn Goudreault

Ian C Scott

W Brent Derry

Avijit Chakrabartty

Anne-Claude Gingras

Frank Sicheri

Affiliations

Soon will be listed here.

Abstract

CCM3 mutations give rise to cerebral cavernous malformations (CCMs) of the vasculature through a mechanism that remains unclear. Interaction of CCM3 with the germinal center kinase III (GCKIII) subfamily of Sterile 20 protein kinases, MST4, STK24, and STK25, has been implicated in cardiovascular development in the zebrafish, raising the possibility that dysregulated GCKIII function may contribute to the etiology of CCM disease. Here, we show that the amino-terminal region of CCM3 is necessary and sufficient to bind directly to the C-terminal tail region of GCKIII proteins. This same region of CCM3 was shown previously to mediate homodimerization through the formation of an interdigitated α-helical domain. Sequence conservation and binding studies suggest that CCM3 may preferentially heterodimerize with GCKIII proteins through a manner structurally analogous to that employed for CCM3 homodimerization.

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