The crystal structure of DR6 in complex with the amyloid precursor protein provides insight into death receptor activation

Abstract

The amyloid precursor protein (APP) has garnered considerable attention due to its genetic links to Alzheimer's disease. Death receptor 6 (DR6) was recently shown to bind APP via the protein extracellular regions, stimulate axonal pruning, and inhibit synapse formation. Here, we report the crystal structure of the DR6 ectodomain in complex with the E2 domain of APP and show that it supports a model for APP-induced dimerization and activation of cell surface DR6. The amyloid precursor protein (APP) is a single-pass transmembrane protein best known for its genetic association with Alzheimer's disease (AD). APP serves as the proteolytic precursor to Aβ, the major peptide component of amyloid plaques in the brains of Alzheimer's patients (Selkoe 2011). Therapeutic strategies to modify APP processing or clear Aβ from plaques in Alzheimer's patients have not yet proven effective (Gandy and DeKosky 2013), encouraging the search for additional approaches for treating AD. This has stimulated interest in understanding the normal physiological role of APP in the developing and adult nervous system in the hope that this will provide new insights into how perturbed APP function may contribute to disease onset and/or progression. These studies have implicated APP in several physiological processes, including axon pruning, synapse formation, axonal transport, and cellular adhesion (Kamal et al. 2001;Priller et al. 2006;Bittner et al. 2009;Nikolaev et al. 2009;Wang et al. 2009). The extracellular domain of APP is comprised of an N-terminal domain termed E1 and a more C-terminal domain termed E2 that are linked via an acidic unstructured sequence and followed by a transmembrane helix and a cytoplasmic region. Previous studies have elucidated the structures of the unbound APP extracellular domains (Wang and Ha 2004;Dahms et al. 2010Dahms et al. , 2012Hoopes et al. 2010;Lee et al. 2011; Xue et al. 2011a,b;Coburger et al. 2013Coburger et al. , 2014. High-affinity binding of APP to death receptor 6 (DR6, also known as TNFRSF21), a death domain-containing member of the extended TNF receptor superfamily (Pan et al. 1998), was recently documented (Nikolaev et al. 2009) and shown to be mediated by the E2 domain of APP (Olsen et al. 2014). DR6 has four cysteine-rich domain (CRD) modules in its extracellular region, followed by a transmembrane domain and death domain in its cytoplasmic region. The structure of the unbound DR6 ectodomain (ECD) (Kuester et al. 2011;Ru et al. 2012) revealed an elongated architecture with a kink between CRD modules 2 and 3. Genetic analysis of DR6 and APP mutant mice showed that the animals share several coincident phenotypes, including behavioral deficits, altered synapse formation, and delayed axon pruning during development or following sensory deprivation Olsen et al. 2014). These and other data Olsen et al. 2014) indicate that APP and DR6 function cell-autonomously and in the same pathway to stimulate axon pruning and synapse elimination. However, how APP and DR6 interact to mediate their actions is poor...

Death Receptor 6 Promotes Wallerian Degeneration in Peripheral Axons

“…Given that this putative ligand would be axon derived, this may be a mechanism for axons to coordinate their degeneration, which could allow macrophages and glia to remove debris efficiently. The ligand for DR6 has remained elusive and it is still widely considered to be an orphan receptor [36,37]. In 2009, it was suggested that an N-terminal fragment of amyloid precursor protein (APP) may serve as a ligand for DR6 [38].…”

“…While it is clear that in several instances APP and DR6 are in the same genetic pathway, it may not be as a ligand receptor pair [7]. A recent crystal structure reveals that the way in which DR6 and APP interact is consistent with a co-receptor relationship [7, 37]. If APP is indeed acting as a co-receptor it will be critical to continue seeking ligands for DR6 in the context of Wallerian degeneration.…”

Physiological role for amyloid precursor protein in adult experience-dependent plasticity

“…Previously, we reported that DR6 is necessary for axonal pruning after sensory loss (6). DR6 has been shown to interact with APP (7,8) to induce an apoptotic pathway (10) that initiates axonal pruning (9). Taken together, these data suggest APP and DR6 coordinate experience-dependent plasticity and axonal pruning in the adult brain.…”

“…Previously, we demonstrated that axonal pruning after sensory deprivation (e.g., selective whisker plucking) requires death receptor 6 (DR6) (6). DR6 interacts with the E2 domain of amyloid precursor protein (APP) (7,8), and together, these proteins initiate an apoptotic cascade that mediates axon pruning in the absence of cell body death during development (8-10). It remains to be determined whether DR6-mediated pruning of axons after sensory deprivation in the adult may also involve APP.…”

The role of the TNF receptors and apoptosis inducing ligands in tumor growth

“…The role of DR6 as an apoptosis-inducing receptor is less clear and perhaps cell type dependent [16]. It is interesting to note that DR6 can bind the amyloid precursor protein via the protein extracellular regions, inhibits synapse formation and is important for APP-induced dimerization and activation of cell surface TNFRSF21/DR6 [40].…”