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Notch Cleavage: Nicastrin Helps Presenilin Make the Final View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Current Biology, Vol. 12, R200–R202, March 19, 2002, ©2002 Elsevier Science Ltd. All rights reserved. PII S0960-9822(02)00749-2 Notch Cleavage: Nicastrin Helps Dispatch Presenilin Make the Final Cut Eric C. Lai Presenilin is thought to be the proteolytic compo- nent of γ-secretase, responsible for the intramem- branous cleavage of substrates that include the activated Notch receptor. Recent studies have iden- S1 S2 tified the novel protein Nicastrin as another essential γ component of the Presenilin/ -secretase complex. S3 NEXT Notch is a transmembrane receptor that is the focal NIC member of a widely utilized, eponymous signal trans- Current Biology duction cascade; it mediates cell–cell interactions and pattern formation in all metazoan organisms examined Figure 1. Summary of Notch cleavage events. to date. Nearly a decade ago, several groups inde- S1 cleavage in the extracellular domain of Notch (red), catal- pendently noticed that a constitutively active Notch ysed by a furin-like convertase, occurs constitutively in the fragment consisting of its intracellular domain (NIC) is Golgi. The two halves are reassembled as an intramolecular nuclearly localized, a provocative observation that heterodimer present at the plasma membrane. Interaction with ligand induces S2 cleavage by a disintegrin/metalloprotease suggested a function for this transmembrane protein (TACE, and possibly Kuzbanian), generating the Notch extra- in the nucleus (reviewed in [1]). Although the evidence cellular truncation (NEXT). NEXT is processed by the γ-secre- for this hypothesis took some years to accumulate, it tase complex (oval), which includes Nicastrin (blue) and is now generally accepted that activation of Notch at Presenilin (green). Nicastrin is a single pass transmembrane the cell surface by ligand triggers proteolytic cleavage protein that might aid in the assembly or trafficking of the γ- and release of NIC, which then translocates to the secretase complex to the plasma membrane and/or help to recruit substrates. Presenilin is an eight-transmembrane nucleus and functions as a transcriptional coactivator. domain, putative aspartyl protease thought to be the catalytic Now a new player has been identified: the novel component of γ-secretase. The order and timing of γ-secre- protein Nicastrin, which recent studies [2–4] show tase/substrate assembly is not well defined, and they may exist plays an important part in the Presenilin-mediated as a complex as Notch is trafficked to the cell surface (i.e., prior cleavage and release of NIC from the plasma to S2 cleavage). However, only the NEXT fragment, and not γ membrane. heterodimeric Notch, is efficiently cleaved by -secretase. S3 cleavage in the transmembrane domain releases NIC, which subsequently translocates to the nucleus. Notch Cleavage: It’s As Easy As S1, S2, S3 Notch processing is unexpectedly complex and particular cleavage has attracted considerable interest includes multiple proteolytic events (Figure 1) referred for two reasons. First, it is the key event that regulates to as the S1, S2 and S3 cleavages (reviewed in [5]). S1 nuclear translocation of NIC and its second life as a cleavage in the extracellular domain of Notch occurs transcriptional coactivator. Second, a processed constitutively in the trans-Golgi network and is carboxy-terminal fragment of the β-amyloid precursor mediated by a furin-like convertase; reassembly of the protein (β-APP) is subject to a highly similar intramem- fragments creates a heterodimeric Notch receptor at branous cleavage, an event that underlies the forma- the cell surface. This event has been most closely tion of cytotoxic plaques found in patients afflicted characterized with respect to mammalian Notch, but with Alzheimer’s disease. Understanding the there is evidence that fly Notch is similarly processed. mechanism of γ-secretase-mediated cleavage is thus S2 cleavage by a disintegrin/metalloprotease occurs potentially of great medical relevance as well. in response to ligand binding and releases the major- ity of the extracellular domain. This cleavage is Presenilin and Nicastrin in S3 Cleavage believed to be mediated by TACE in vertebrates and A wealth of studies using invertebrate and vertebrate may be mediated by the related but distinct protein model systems demonstrated that Presenilin is a key Kuzbanian in Drosophila, although the precise role of component of γ-secretase which is biochemically the latter protein is controversial at present. required for Notch S3 cleavage and genetically The resulting membrane-anchored fragment, essential for Notch signal transduction (reviewed in referred to as Notch extracellular truncation (NEXT), is [5]). Presenilin is an eight-transmembane domain, subject to intramembranous S3 cleavage by γ-secre- putative aspartyl protease which is widely thought to tase, which finally releases NIC. The mechanism of this be the enzyme that cleaves γ-secretase substrates. Presenilin co-purifies with the γ-secretase complex 545 Life Sciences Addition, University of California, and is labeled by transition-state analogue inhibitors Department of Molecular and Cell Biology, Berkeley, of γ-secretase. However, direct demonstration of California 94720-3200, USA. [email protected] Presenilin-mediated substrate cleavage in vitro has Current Biology R201 not yet been possible, probably because of the strictly cell autonomously in vivo, and that cells do not requirement for additional factors in the large require Nicastrin to send the Notch signal [2,3]. Thus, ~2000 kD γ-secretase complex. Nicastrin is generally required for Notch signaling and In a satisfying convergence of genetic and functions in signal-receiving cells in Drosophila. biochemical approaches, orthologs of a novel single- To determine the site of Nicastrin function in signal pass transmembrane protein involved in Notch signal reception, these researchers took advantage of two transduction and γ-secretase activity were recently types of constitutively active Notch deletion variant isolated independently from worms and humans. This previously used to characterize Notch and Presenilin protein, first known as APH-2, was identified from a function. Although these variants signal independently screen for maternal-effect mutants of the nematode of ligand in wild-type tissue, they differ in their require- Caenorhabditis elegans that have phenotypes resem- ment for Presenilin. The first, ∆ECN, resembles NEXT bling those resulting from mutations in GLP-1, one of in that it lacks most of the extracellular domain but two nematode Notch receptors [6]. APH-2 localizes to remains membrane anchored; it requires Presenilin for cell-surface membranes and is required for GLP-1- S3 cleavage and access to the nucleus. The second, mediated cell–cell interactions in the early embryo. It NIC, is soluble, translocates freely to the nucleus, and is subsequently required for signaling by LIN-12, the signals independently of Presenilin. These Notch other worm Notch receptor, during development of derivatives display identical requirements for Prese- the somatic gonad [7]. nilin and Nicastrin for access to the nucleus and signal Complementary biochemical studies [8] identified transducing activity, indicating that Nicastrin also the human homolog of APH-2, Nicastrin, as a protein functions in S3 cleavage of Notch (Figure 1) [2–4]. that could be stoichiometrically immunopurified with These genetic data were substantiated with biochem- Presenilin. Yu et al. [8] named the protein after the ical data demonstrating an accumulation of NEXT in Italian village Nicastro, home to members of an the absence of either Nicastrin or Presenilin. Although extended family that were key to studies that eventu- the cellular location of S3 cleavage has been the ally linked mutations in the two human presenilin genes subject of debate, nicastrin and presenilin follicle cell to the most frequent forms of familial Alzheimer’s clones accumulate NEXT at the apical membrane, disease. Nicastrin forms a ternary complex with Prese- suggesting that the plasma membrane is indeed the nilin and the γ-secretase substrates NEXT or carboxy- location of S3 cleavage [3]. terminal β-APP [8,9]. Furthermore, misexpression of various forms of Nicastrin was found to modulate pro- Possible Functions of Nicastrin cessing of β-APP, indicating a functional link between Nicastrin exhibits independent interactions with Nicastrin and γ-secretase. Finally, Nicastrin function Presenilin and substrates, which led to the proposition has been conserved, as human Nicastrin can partially that it might help to recruit substrates to the γ-secre- complement the aph-2 mutant phenotype [7]. tase complex for processing by Presenilin [8,9]. Sur- In spite of these compelling links between Nicastrin prisingly, Presenilin-dependent intramembranous and Notch signaling, some important connections cleavage does not absolutely require any specific remained to be made. For example, misexpression of sequence motif. Instead, a primary determinant various Nicastrin mutants that strongly affect β-APP appears to be that the size of the substrate extracel- processing only mildly affect Notch processing [9]. lular domain be small [10]. As some 95% of Nicastrin Also, aph-2 mutations affect some, but not all settings is located extracellularly, it was speculated that Nicas- of Notch activity [7]. These negative data could be trin might
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