Fe65like

Fe65-like refers to a subgroup of adaptor proteins related to Fe65 that share similar domain organization and functional relationships with the amyloid precursor protein (APP). In humans, the best characterized members are APBB2 and APBB3, commonly called Fe65-like protein 2 and Fe65-like protein 3. These proteins are thought to function as cytoplasmic and nuclear adaptors that mediate signaling downstream of APP and related receptors.

A defining feature of Fe65-like proteins is the presence of phosphotyrosine-binding (PTB) domains, which enable binding to the NPXY motifs within the cytoplasmic tail of APP and other partners. Through these interactions, Fe65-like proteins can participate in APP-derived signaling cascades that influence receptor trafficking, processing, and, when AICD (the APP intracellular domain) is released, transcriptional regulation in the nucleus. In many models, Fe65-like proteins form complexes with APP-derived fragments and transcriptional co-activators such as Tip60, contributing to the regulation of gene expression.

Expression patterns for Fe65-like proteins are broad but are notably enriched in neural tissues, where APP signaling plays a prominent role in development and synaptic function. The precise physiological roles of Fe65-like proteins continue to be elucidated, but they are generally viewed as modulators of protein interaction networks that connect membrane signaling to nuclear transcriptional responses.

In disease contexts, alterations in APP signaling and Fe65-family interactions have been explored in relation to Alzheimer’s disease, where AICD-driven transcriptional programs may influence pathology. Overall, Fe65-like proteins are considered adaptor proteins that coordinate protein–protein interactions within APP signaling networks, thereby shaping cellular responses to APP processing.

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