Functional analysis of CASK transcript variants expressed in human brain
Fig 9
Effect of alternative splice inserts on structural features of CASK.
A: Role of the splice insert encoded by exon 11 in the CASK-SAP97 complex. The structure of CASK L27.1 in complex with the single L27 domain of SAP97 contains the additional residues of the splice insert encoded by exon 11 (magenta). The splice insert extents the first helix in L27.1 of CASK, allowing for a hydrophobic interaction of A343 in CASK with I40 of SAP97. A lack of this insert brings highly flexible residues like P, G, T and S to this position, likely giving that helix-turn-helix cluster a higher degree of freedom to stabilize this conformation. B: Possible conformational changes of CASK domains, as suggested by structural analysis of other MAGUKs. A compact conformation (left), where CaMK and L27 domains attach to an extended PDZ-SH3-GK module (PSG) and all splice inserts are buried within the complex would only allow binding to CaMK. An extended PSD-95 like conformation (middle) would allow binding to most CASK binding partners. A PALS-like conformation with an U-formed PSG module (right) is required to bind to TBR/Cinap and the cytosolic C-terminus of Nrxn (middle) would allow binding to most CASK binding partners. Note that Mint and liprin compete for the same binding site in the CaMK domain; however, in the presence of neurexin, liprin binds to an alternative site, allowing for the formation of a tetratrameric complex (Nrxn, CASK, Mint and liprin), as described in ref. [26].