AI Article Synopsis
- CCM3 mutations lead to cerebral cavernous malformations (CCMs), but the exact mechanism is not well understood.
- There is evidence that CCM3 interacts with certain protein kinases (GCKIII subfamily) involved in cardiovascular development, especially in zebrafish.
- The study reveals that the amino-terminal part of CCM3 is crucial for binding to GCKIII proteins, and both homodimerization and possible heterodimerization mechanisms are suggested in their interactions.
Article 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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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3137079 | PMC |
| http://dx.doi.org/10.1074/jbc.M110.213777 | DOI Listing |
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