title: CCM3/PDCD10 heterodimerizes with germinal center kinase III (GCKIII) proteins using a mechanism analogous to CCM3 homodimerization.
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.
authors.affiliation: Centre for Systems Biology, Samuel Lunenfeld Research Institute at Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
authors.forename: Derek F
authors.initials: DF
authors.lastname: Ceccarelli
authors.forename: Rob C
authors.initials: RC
authors.lastname: Laister
authors.forename: Vikram Khipple
authors.initials: VK
authors.lastname: Mulligan
authors.forename: Michelle J
authors.initials: MJ
authors.lastname: Kean
authors.forename: Marilyn
authors.initials: M
authors.lastname: Goudreault
authors.forename: Ian C
authors.initials: IC
authors.lastname: Scott
authors.forename: W Brent
authors.initials: WB
authors.lastname: Derry
authors.forename: Avijit
authors.initials: A
authors.lastname: Chakrabartty
authors.forename: Anne-Claude
authors.initials: AC
authors.lastname: Gingras
authors.forename: Frank
authors.initials: F
authors.lastname: Sicheri
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002319:Cardiovascular System / Q000196:embryology; D000081410:Germinal Center Kinases; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D038081:Organogenesis / Q000502:physiology; D055503:Protein Multimerization / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics; D029961:Zebrafish Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D000081410:Germinal Center Kinases; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D029961:Zebrafish Proteins; C542753:pdcd10a protein, zebrafish; D017346:Protein Serine-Threonine Kinases