title: GTP binding and intramolecular regulation by the ROC domain of Death Associated Protein Kinase 1.
abstract: The ROCO proteins are a family of large, multidomain proteins characterised by the presence of a Ras of complex proteins (ROC) domain followed by a COR, or C-terminal of ROC, domain. It has previously been shown that the ROC domain of the human ROCO protein Leucine Rich Repeat Kinase 2 (LRRK2) controls its kinase activity. Here, the ability of the ROC domain of another human ROCO protein, Death Associated Protein Kinase 1 (DAPK1), to bind GTP and control its kinase activity has been evaluated. In contrast to LRRK2, loss of GTP binding by DAPK1 does not result in loss of kinase activity, instead acting to modulate this activity. These data highlight the ROC domain of DAPK1 as a target for modifiers of this proteins function, and casts light on the role of ROC domains as intramolecular regulators in complex proteins with implications for a broad range of human diseases.
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Jebelli
authors.forename: Sybille
authors.initials: S
authors.lastname: Dihanich
authors.forename: Laura
authors.initials: L
authors.lastname: Civiero
authors.forename: Claudia
authors.initials: C
authors.lastname: Manzoni
authors.forename: Elisa
authors.initials: E
authors.lastname: Greggio
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Lewis
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D041883:Chlorobium / Q000737:chemistry; D064550:Death-Associated Protein Kinases; D006160:Guanosine Triphosphate / Q000737:chemistry / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D062105:Molecular Docking Simulation; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D021381:Protein Transport
chemical_list: D051017:Apoptosis Regulatory Proteins; D001426:Bacterial Proteins; D006160:Guanosine Triphosphate; C579096:DAPK1 protein, human; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases