Journal
CELL COMMUNICATION AND SIGNALING
Volume 14, Issue -, Pages -Publisher
BMC
DOI: 10.1186/s12964-016-0140-3
Keywords
Analytical ultracentrifugation; Cell signaling; Crystal structure; Neuroscience; Nuclear magnetic resonance; Protein structure; Scaffold protein
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Funding
- Canadian Institutes of Health Research [MOP-81250]
- Canada Research Chair in Molecular and Cellular Neuroscience
- King Abdullah University of Science and Technology
- NSF [DAC-1339649, TG-MCB070039]
- San Antonio Cancer Institute [P30 CA054174]
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Background: CASKIN2 is a homolog of CASKIN1, a scaffolding protein that participates in a signaling network with CASK (calcium/calmodulin-dependent serine kinase). Despite a high level of homology between CASKIN2 and CASKIN1, CASKIN2 cannot bind CASK due to the absence of a CASK Interaction Domain and consequently, may have evolved undiscovered structural and functional distinctions. Results: We demonstrate that the crystal structure of the Sterile Alpha Motif (SAM) domain tandem (SAM1-SAM2) oligomer from CASKIN2 is different than CASKIN1, with the minimal repeating unit being a dimer, rather than a monomer. Analytical ultracentrifugation sedimentation velocity methods revealed differences in monomer/dimer equilibria across a range of concentrations and ionic strengths for the wild type CASKIN2 SAM tandem and a structure-directed double mutant that could not oligomerize. Further distinguishing CASKIN2 from CASKIN1, EGFP-tagged SAM tandem proteins expressed in Neuro2a cells produced punctae that were distinct both in shape and size. Conclusions: This study illustrates a new way in which neuronal SAM domains can assemble into large macromolecular assemblies that might concentrate and amplify synaptic responses.
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