Mapping of Interaction Domains Mediating Binding between BACE1 and RTN/Nogo Proteins

He, Wanxia; Hu, Xiangyou; Shi, Qi; Zhou, Xiangdong; Lu, Yifeng; Fisher, Christopher J.; Yan, Riqiang

doi:10.1016/j.jmb.2006.07.094

Cited by 38 publications

(37 citation statements)

References 46 publications

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“…Because both C-terminal tails face the cytosolic side, the same topological orientation makes this binding compatible. As discussed previously (12), this binding is important for the inhibition of BACE1 by RTN3. If the binding is disrupted, its inhibition of BACE1 is abolished, and we found that the RTN3 mutants with disruption in either TM1 or TM2 failed to affect the production of A␤ (data not shown), consistent with our previous conclusion (12).…”

Section: Discussionmentioning

confidence: 68%

“…We have recently mapped the residues near the C-terminal tail of RTN3 that are responsible for its interaction with BACE1 (12). Similarly, a short C-terminal stretch more proximal to the TM domain of BACE1 is responsible for the binding of BACE1 to RTN3.…”

Section: Discussionmentioning

confidence: 99%

“…RTN4, or its more popular acronym Nogo, is identified as a critical inhibitory molecule in axonal growth and regeneration (5,6). Recently, reticulon proteins (including Nogo) have been shown to interact with ␤-secretase, also known as ␤-site APP-cleaving enzyme 1 (BACE1) (7)(8)(9)(10), and this interaction negatively modulates the enzymatic activity of BACE1 (11)(12)(13). Among the RTNs, we have paid particular attention to RTN3 because of its strong inhibitory effects on BACE1 activity and high expression by neurons.…”

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confidence: 99%

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The Membrane Topology of RTN3 and Its Effect on Binding of RTN3 to BACE1

Shi

et al. 2007

Journal of Biological Chemistry

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Reticulon 3 (RTN3) has recently been shown to modulate Alzheimer BACE1 activity and to play a role in the formation of dystrophic neurites present in Alzheimer brains. Despite the functional importance of this protein in Alzheimer disease pathogenesis, the functional correlation to the structural domain of RTN3 remained unclear. RTN3 has two long transmembrane domains, but its membrane topology was not known. We report here that the first transmembrane domain dictates membrane integration and its membrane topology. RTN3 adopts a -shape structure with two ends facing the cytosolic side. Subtle changes in RTN3 membrane topology can disrupt its binding to BACE1 and its inhibitory effects on BACE1 activity. Thus, the determination of RTN3 membrane topology may provide an important structural basis for our understanding of its cellular functions. Reticulon (RTN)2 proteins are a group of membrane-bound proteins that are largely localized in the endoplasmic reticulum (ER) (1, 2), perhaps more restricted to the tubular ER (3). RTNs exist in plants, fungi, and animals (4). In mammalian genomes, four independent reticulon genes, rtn1 to rtn4, have been identified to encode a large number of gene products (1, 2). All RTNs are composed of a variable length of N-terminal domain, which is completely divergent among RTN members, and a highly conserved RTN homology domain (RHD) that is unique to this family of proteins. Within the RHD, there exist two long stretches (28 -36 amino acids) of hydrophobic residues, and each is expected to embed RTNs in the membrane.The divergent N-terminal domain among RTNs potentially allows each RTN member to exert its specific function. RTN4, or its more popular acronym Nogo, is identified as a critical inhibitory molecule in axonal growth and regeneration (5, 6). Recently, reticulon proteins (including Nogo) have been shown to interact with ␤-secretase, also known as ␤-site APP-cleaving enzyme 1 (BACE1) (7-10), and this interaction negatively modulates the enzymatic activity of BACE1 (11-13). Among the RTNs, we have paid particular attention to RTN3 because of its strong inhibitory effects on BACE1 activity and high expression by neurons. RTN3 is localized not only in the ER compartment but also in the Golgi (11, 14), axons, dendrites, and growth cone (15). The localization of RTN3 in the neuritic region suggests its potential role in neuritic functions. Most recently, we have demonstrated that RTN3 also plays a role in the formation of dystrophic neurites in Alzheimer brains (15).Because of the important role of RTN3 in Alzheimer pathogenesis, we set out to study the structure and function of RTN3. We report herein that the first transmembrane stretch or domain (TM1) is important for the membrane insertion of RTN3. Disruption of the TM1 of RTN3 results in misfolding of the mutant protein and failure to integrate the protein into the membrane. We also show that RTN3 adopts a -shape membrane topology with both the N-and C-terminal ends facing the cytosolic side. Knowledge from this study will be...

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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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The Membrane Topology of RTN3 and Its Effect on Binding of RTN3 to BACE1

Shi

et al. 2007

Journal of Biological Chemistry

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“…Reduced level of protein kinase C alpha (Prkca) is related to an altered App secretion in fibroblasts from AD patients (Benussi et al, 1998). Another associated gene, membrane-bound reticulon (Rtn), interacts with BACE1, which is a membrane-bound aspartyl protease that specifically cleaves protein APP at the beta secretase site and negatively modulates BACE1 activity by preventing access of BACE1 to its cellular App substrate (He et al, 2006). It is likely that many of the remaining genes in this network may also have functional roles in AD.…”

Section: Genetic Regulatory Network Of Appmentioning

confidence: 99%

Genetic Regulatory Network Analysis forAppBased on Genetical Genomics Approach

Wang

Chen

Wang

et al. 2009

Experimental Aging Research

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“…BACE1 interacts with RTNs on the membrane in a region near their C-terminal sequences (33,34). Increased expression of RTNs significantly reduces the production of A␤ in both cultured cells and transgenic mouse models (23,(35)(36)(37)(38).…”

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confidence: 99%

Increased Expression of Reticulon 3 in Neurons Leads to Reduced Axonal Transport of β Site Amyloid Precursor Protein-cleaving Enzyme 1

Deng

Tan

et al. 2013

Journal of Biological Chemistry

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Background: Axonal transport of BACE1 and the regulation of BACE1 synaptic localization remain to be fully characterized. Results: Colocalization of BACE1 with synaptophysin was reduced by overexpression of RTN3. This reduction was due to reduced BACE1 axonal transport. Conclusion: Increased interaction of RTN3 with BACE1 in the soma impacts axonal transport of BACE1. Significance: Changes of BACE1 synaptic localization potentially alter synaptic A␤ generation and amyloid deposition.

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Mapping of Interaction Domains Mediating Binding between BACE1 and RTN/Nogo Proteins

Cited by 38 publications

References 46 publications

The Membrane Topology of RTN3 and Its Effect on Binding of RTN3 to BACE1

The Membrane Topology of RTN3 and Its Effect on Binding of RTN3 to BACE1

Genetic Regulatory Network Analysis forAppBased on Genetical Genomics Approach

Increased Expression of Reticulon 3 in Neurons Leads to Reduced Axonal Transport of β Site Amyloid Precursor Protein-cleaving Enzyme 1

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