A Small Molecule Targeting the Transmembrane Domain of Death Receptor p75NTR Induces Melanoma Cell Death and Reduces Tumor Growth

Goh, Eddy T. H.; Lin, Zhiang; Ahn, Bo Young; Lopes-Rodrigues, Vanessa; Dang, Ngoc Ha; Salim, Shuhailah; Berger, Bryan W.; Dymock, Brian; Senger, Donna L.; Ibáñez, Carlos F.

doi:10.1016/j.chembiol.2018.09.007

Cited by 20 publications

(35 citation statements)

References 41 publications

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“…This demonstrates that the exogenous TM domain alone can create effects similar to those seen in the cellular experiments. In addition to recent work completed in suppression of hyperactive immune cells (32), inhibition or suppression of tumor growth in several cancers (33)(34)(35), and inhibition of oncogenic activation induced by Epstein-Barr virus (36), these experiments further support the notion that the effects seen are specific to destabilizing TM interactions.…”

Section: Discussionsupporting

confidence: 57%

“…TM peptides that disrupt ErbB2 TM dimerization were found to reduce tumor cell growth and metastasis (39). Other studies have demonstrated the potential use of small molecules that disrupt TM domain oligomerization to suppress tumor growth in glioma and metastasis by targeting the TM of plexin A1 (34) and to inhibit tumor growth in melanoma by TM interactions in p75 NTR (33). The results presented may further help in development or improvement of antivirals and other TM-targeting therapeutics.…”

Section: Discussionmentioning

confidence: 82%

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A Hydrophobic Target: Using the Paramyxovirus Fusion Protein Transmembrane Domain To Modulate Fusion Protein Stability

Barrett

Webb

Dutch

2019

J Virol

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Enveloped viruses utilize surface glycoproteins to bind and fuse with a target cell membrane. The zoonotic Hendra virus (HeV), a member of the family Paramyxoviridae, utilizes the attachment protein (G) and the fusion protein (F) to perform these critical functions. Upon triggering, the trimeric F protein undergoes a large, irreversible conformation change to drive membrane fusion. Previously, we have shown that the transmembrane (TM) domain of the F protein, separate from the rest of the protein, is present in a monomer-trimer equilibrium. This TM-TM association contributes to the stability of the prefusion form of the protein, supporting a role for TM-TM interactions in the control of F protein conformational changes. To determine the impact of disrupting TM-TM interactions, constructs expressing the HeV F TM with limited flanking sequences were synthesized. Coexpression of these constructs with HeV F resulted in dramatic reductions in the stability of F protein expression and fusion activity. In contrast, no effects were observed when the HeV F TM constructs were coexpressed with the nonhomologous parainfluenza virus 5 (PIV5) fusion protein, indicating a requirement for specific interactions. To further examine this, a TM peptide homologous to the PIV5 F TM domain was synthesized. Addition of the peptide prior to infection inhibited infection with PIV5 but did not significantly affect infection with human metapneumovirus, a related virus. These results indicate that targeted disruption of TM-TM interactions significantly impact viral fusion protein stability and function, presenting these interactions as a novel target for antiviral development. IMPORTANCE Enveloped viruses require virus-cell membrane fusion to release the viral genome and replicate. The viral fusion protein triggers from the pre-to the postfusion conformation, an essentially irreversible change, to drive membrane fusion. We found that small proteins containing the TM and a limited flanking region homologous to the fusion protein of the zoonotic Hendra virus reduced protein expression and fusion activity. The introduction of exogenous TM peptides may displace a TM domain, disrupting native TM-TM interactions and globally destabilizing the fusion protein. Supporting this hypothesis, we showed that a sequence-specific transmembrane peptide dramatically reduced viral infection in another enveloped virus model, suggesting a broader inhibitory mechanism. Viral fusion protein TM-TM interactions are important for protein function, and disruption of these interactions dramatically reduces protein stability.

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Section: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 82%

A Hydrophobic Target: Using the Paramyxovirus Fusion Protein Transmembrane Domain To Modulate Fusion Protein Stability

Barrett

Webb

Dutch

2019

J Virol

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“…We have recently provided proof-of-principle of this general concept in a recent report (Goh et al, 2018), paving the way for larger scale screenings of compound collections that may enable the discovery of substances mimicking the effects of the C259A mutation.…”

Section: Discussionmentioning

confidence: 99%

Inactive variants of death receptor p75^NTRreduce Alzheimer’s neuropathology by interfering with APP internalization

Ibáñez

Goh

et al. 2020

Preprint

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A prevalent model of Alzheimer's disease (AD) pathogenesis postulates the generation of neurotoxic fragments derived from the amyloid precursor protein (APP) after its internalization to endocytic compartments. However, the molecular pathways that regulate APP internalization and intracellular trafficking in neurons are unknown.Here we report that 5xFAD mice, an animal model of AD, expressing signalingdeficient variants of the p75 neurotrophin receptor (p75 NTR ) show greater neuroprotection from AD neuropathology than animals lacking this receptor. p75 NTR knock-in mice lacking the death domain or transmembrane Cys 259 showed lower levels of Aβ species, amyloid plaque burden, gliosis, mitochondrial stress and neurite dystrophy than global knock-outs. Strikingly, long-term synaptic plasticity and memory, which are completely disrupted in 5xFAD mice, were fully recovered in the knock-in mice. Mechanistically, we found that p75 NTR interacts with APP and regulates its internalization in hippocampal neurons. Inactive p75 NTR variants internalized much slower and to lower levels than wild type p75 NTR , favoring nonamyloidogenic APP cleavage by reducing APP internalization and colocalization with BACE1, the critical protease for generation of neurotoxic APP fragments. These results reveal a novel pathway that directly and specifically regulates APP internalization, amyloidogenic processing and disease progression, and suggest that inhibitors targeting the p75 NTR transmembrane domain may be an effective therapeutic strategy in AD. generation of all BACE-derived products, including Aβ, and constitutes the nonamyloidogenic pathway in APP processing. Cleavage by alpha-secretase generates a soluble N-terminal fragment (sAPPα) and a C-terminal stub (sCTFα) that can be further processed by gamma-secretase.Recent studies have indicated that, while cleavage by alpha secretases occurs at the plasma membrane, proteolytic processing by BACE requires APP internalization from the cell surface and thus mainly takes places in intracellular, endocytic compartments (Haass et al, 2012). Several studies have linked APP internalization to Aβ production (Koo & Squazzo, 1994; Selkoe et al, 1996), and complementary lines of evidence support this notion, including the requirement of low pH for BACE Ibáñez CF & Simi A (2012) p75 neurotrophin receptor signaling in nervous system injury and degeneration: paradox and opportunity. Trends Neurosci 35: 431-440 Karran E, Mercken M & De Strooper B (2011) The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics. Nat Rev Drug (2012) The β-secretase-derived C-terminal fragment of βAPP, C99, but not Aβ, is a key contributor to early intraneuronal lesions in triple-transgenic mouse hippocampus.

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“…Similar peptide library design approaches have proven successful at identifying and selecting peptides to inhibit viral TM domain dimerization as well as transmembrane receptor dimerization (32,33). The degenerative oligonucleotide sequence corresponding to the designed TM binder consensus peptide sequence ( Figure 6A) was subcloned in fusion with AraC* to be tested against WT PTPRJ-AraC, using the DN-AraTM assay (34). After cotransforming these constructs into E. coli, individual colonies were tested for GFP emission.…”

Section: Design and Identification Of A Tm Peptide Sequence Capable Omentioning

confidence: 99%

Disrupting the Transmembrane Domain Oligomerization of Protein Tyrosine Phosphatase Receptor J Promotes its Activity in Cancer Cells

Bloch

Sikorski

Pontoriero

et al. 2019

Preprint

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Despite the critical regulatory roles that receptor protein tyrosine phosphatases (RPTP) play in mammalian signal transduction, the detailed structural basis for the regulation of their catalytic activity is not fully understood, nor are they generally therapeutically targetable. It is due, in part, to the lack of known natural ligands or selective agonists. In contrast to conventional structure-function relationship for receptor tyrosine kinases (RTKs), the activity of RPTPs has been reported to be suppressed by dimerization, which may prevent their access to their RTK substrates. We report here that: (i) homodimerization of PTPRJ (also known as DEP-1) is regulated by specific transmembrane (TM) residues, and (ii) disrupting these interactions can destabilize full-length PTPRJ homodimerization in cells, reduce the phosphorylation of EGFR (a known substrate) and downstream signaling effectors, antagonize EGFR-driven cell phenotypes, and promote substrate access. We demonstrate these points in human cancer cells using both mutational studies and through the identification of a peptide designed to bind to the PTPRJ TM domain. This peptide is the first example of such allosteric agonist of RPTPs. This study, therefore, provides not only fundamental structure-function insights on how PTPRJ activity is tuned by TM interactions in cells but also opportunities to develop a unique class of agents that could be used as tools to probe RPTPs signaling regulating mechanisms or for therapeutic purposes in cancers driven by RTK signaling.

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A Small Molecule Targeting the Transmembrane Domain of Death Receptor p75NTR Induces Melanoma Cell Death and Reduces Tumor Growth

Cited by 20 publications

References 41 publications

A Hydrophobic Target: Using the Paramyxovirus Fusion Protein Transmembrane Domain To Modulate Fusion Protein Stability

A Hydrophobic Target: Using the Paramyxovirus Fusion Protein Transmembrane Domain To Modulate Fusion Protein Stability

Inactive variants of death receptor p75^NTRreduce Alzheimer’s neuropathology by interfering with APP internalization

Disrupting the Transmembrane Domain Oligomerization of Protein Tyrosine Phosphatase Receptor J Promotes its Activity in Cancer Cells

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A Small Molecule Targeting the Transmembrane Domain of Death Receptor p75NTR Induces Melanoma Cell Death and Reduces Tumor Growth

Cited by 20 publications

References 41 publications

A Hydrophobic Target: Using the Paramyxovirus Fusion Protein Transmembrane Domain To Modulate Fusion Protein Stability

A Hydrophobic Target: Using the Paramyxovirus Fusion Protein Transmembrane Domain To Modulate Fusion Protein Stability

Inactive variants of death receptor p75NTRreduce Alzheimer’s neuropathology by interfering with APP internalization

Disrupting the Transmembrane Domain Oligomerization of Protein Tyrosine Phosphatase Receptor J Promotes its Activity in Cancer Cells

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Product

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Inactive variants of death receptor p75^NTRreduce Alzheimer’s neuropathology by interfering with APP internalization