Abstract
AIDA1 links persistent chemical signaling events occurring at the neuronal synapse with global changes in gene expression. Consistent with its role as a scaffolding protein, AIDA1 is composed of several protein-protein interaction domains. Here we report the NMR structure of the carboxy terminally located phosphotyrosine binding domain (PTB) that is common to all AIDA1 splice variants. A comprehensive survey of peptides identified a consensus sequence around an NxxY motif that is shared by a number of related neuronal signaling proteins. Using peptide arrays and fluorescence based assays, we determined that the AIDA1 PTB domain binds amyloid protein precursor (APP) in a similar manner to the X11/Mint PTB domain, albeit at reduced affinity (∼10 µM) that may allow AIDA1 to effectively sample APP, as well as other protein partners in a variety of cellular contexts.
Highlights
Neurons receive chemical signals through a collection of over four hundred proteins that are organized into a network termed the postsynaptic density (PSD) [1]
The surface of the phosphotyrosine binding domain (PTB) model was scanned for exposed aromatics and compared to a sequence alignment consisting of the PTB domains from X11, Numb [19] and Fe65 [20]
Of the sixteen aromatics in the AIDA1 PTB domain, Y6, F16, F24, Y70, and Y131 were selected as candidates that were most likely to be surface-exposed (Figure 1a)
Summary
Neurons receive chemical signals through a collection of over four hundred proteins that are organized into a network termed the postsynaptic density (PSD) [1]. AIDA1, a prominent member of the PSD, is edited into at least five isoforms, all of which contain two sterile alpha motif (SAM) domains and a PTB domain [2]. Together, these domains suggest a role for AIDA1 as a scaffolding molecule that collates proteins at the synapse through multiple protein-protein interactions. While AIDA1 is predominantly expressed in brain, a related protein, Odin (ANKS1A), with the same domain organization, is more ubiquitously expressed and serves as an adaptor modulating the signaling outcomes of epidermal derived growth factor receptor (EGFR), platelet derived growth factor receptor (PDGFR) and ephrin A8 receptor tyrosine kinase [4]
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