Proteolytic ectodomain shedding of membrane proteins in mammals—hardware, concepts, and recent developments

Abstract

Proteolytic removal of membrane protein ectodomains (ectodomain shedding) is a post-translational modification that controls levels and function of hundreds of membrane proteins. The contributing proteases, referred to as sheddases, act as important molecular switches in processes ranging from signaling to cell adhesion. When deregulated, ectodomain shedding is linked to pathologies such as inflammation and Alzheimer's disease. While proteases of the "a disintegrin and metalloprotease" (ADAM) and "beta-site APP cleaving enzyme" (BACE) families are widely considered as sheddases, in recent years a much broader range of proteases, including intramembrane and soluble proteases, were shown to catalyze similar cleavage reactions. This review demonstrates that shedding is a fundamental process in cell biology and discusses the current understanding of sheddases and their substrates, molecular mechanisms and cellular localizations, as well as physiological functions of protein ectodomain shedding. Moreover, we provide an operational definition of shedding and highlight recent conceptual advances in the field. While new developments in proteomics facilitate substrate discovery, we expect that shedding is not a rare exception, but rather the rule for many membrane proteins, and that many more interesting shedding functions await discovery.

The localization of chitin synthase mediates the patterned deposition of chitin in developing Drosophila bristles

“…(Lichtenthaler et al, 2018;van Niel 581 et al, 2018)). In most cases the shed material is an ectodomain that is released due to proteolysis 582 (Lichtenthaler et al, 2018). Such a shedding mechanism could explain the shedding of the NeonGreen 583 component; however, it cannot explain our observation that most puncta stained with both an anti-NG 584 antibody and an antibody directed against an internal and cytoplasmic region of Kkv.…”

“…The shedding of membrane proteins is not a rare phenomenon (e.g. (Lichtenthaler et al, 2018;van Niel 581 et al, 2018)). In most cases the shed material is an ectodomain that is released due to proteolysis 582 (Lichtenthaler et al, 2018).…”

Nr CAM is a marker for substrate‐selective activation of ADAM 10 in Alzheimer's disease

“…Despite the positive outcome of the acitretin study, a key question is the safety profile of prolonged ADAM10 activation. This is of particular concern, because ADAM10 cleaves numerous other substrates besides APP—generally referred to as ectodomain shedding (Lichtenthaler et al , )—, both during embryonic development and in different adult tissues, including the adult brain (Saftig & Lichtenthaler, ; Kuhn et al , ). One of its major substrates in vivo is the Notch receptor, which requires ADAM10 cleavage for its ligand‐induced signal transduction (Pan & Rubin, ; Bozkulak & Weinmaster, ; van Tetering et al , ).…”

Mouse brain proteomics establishes MDGA1 and CACHD1 as in vivo substrates of the Alzheimer protease BACE1

“…Ectodomain shedding of membrane proteins is a basic cellular process controlling the communication between cells, including in the brain . Upon shedding, the extracellular domain of a membrane protein is proteolytically cleaved off and released from cells.…”

“…Ectodomain shedding of membrane proteins is a basic cellular process controlling the communication between cells, including in the brain. 1 Upon shedding, the extracellular domain of a membrane protein is proteolytically cleaved off and released from cells. The contributing proteases, referred to as sheddases, are mostly themselves membrane-bound enzymes and often do not only cleave a single substrate, but numerous different ones.…”