Novel aspects of the apolipoprotein-E receptor family: regulation and functional role of their proteolytic processing

Studies related to the functional and regulatory aspects of proteolytic processing are of interest to cell biologists, developmental biologists and investigators who work on human diseases. Much of what is known about this topic derives from the study of the proteolytic processing of the amyloid precursor protein (APP), which is involved in the pathology of Alzheimer’s disease, and of the Notch protein and its Delta ligand, which play roles during embryonic development and in biologic processes in the adult. The proteolytic processing of plasma membrane receptor proteins is under the control of different enzymes that are responsible for releasing the ectodomain into the extracellular environment, where it has the potential to function as a signaling molecule and/or regulate the availability of the receptor’s ligand. Following shedding of the ectodomain, the γ-secretase enzymatic complex cleaves the transmembrane domain and releases the cytoplasmic domain (ICD) of the receptor. The ICD can function in the cytoplasm and/or at the nucleus. Members of the low-density lipoprotein receptor (LDLR) family are endocytic-signaling proteins that perform a wide variety of physiologic functions during development and in the adult life. In addition these receptors have been implicated in a variety of diseases in adults. The prototypic receptor for this family of proteins is the LDLR itself. Besides their binding to apolipoproteins, these receptors bind many ligands that are destined for internalization and degradation. Some ligands have signaling properties. The proteolytic processing of certain members of the LDLR family not only controls receptor availability at the cell surface but also has functional consequences that amplify the spectrum of roles that these receptors perform. In addition, many complex regulatory mechanisms control the proteolytic processing of these receptors.