Exogenous Agents that Target Transmembrane Domains of Proteins

Yin, Hang

doi:10.1002/anie.200704780

Cited by 20 publications

(16 citation statements)

References 85 publications

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“…That C99 forms a complex with cholesterol, which likely leads to its raft localization, suggests that drug-like molecules that can inhibit complex formation between C99/APP and cholesterol might provide a way of avoiding Aβ production. There is evidence that drug-like molecules can be developed that act by specifically-recognizing and binding to single-span membrane proteins(107;108), suggesting that this approach is feasible.…”

Section: Therapeutic Implications Of Complex Formation Between C99/apmentioning

confidence: 99%

Direct binding of cholesterol to the amyloid precursor protein: An important interaction in lipid–Alzheimer's disease relationships?

Beel

Sakakura

Barrett

et al. 2010

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

154

229

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SummaryIt is generally believed that cholesterol homoeostasis in the brain is both linked to and impacted by Alzheimer's disease (AD). For example, elevated levels of cholesterol in neuronal plasma and endosome membranes appears to be a pro-amyloidogenic factor. The recent observation that the Cterminal transmembrane domain (C99, also known as the β-CTF) of the amyloid precursor protein (APP) specifically binds cholesterol helps to tie together previously loose ends in the web of our understanding of Alzheimer's-cholesterol relationships. In particular, binding of cholesterol to C99 appears to favor the amyloidogenic pathway in cells by promoting localization of C99 in lipid rafts. In turn, the products of this pathway-amyloid-β and the intracellular domain of the APP (AICD) -may down-regulate ApoE-mediated cholesterol uptake and cholesterol biosynthesis. If confirmed, this negative-feedback loop for membrane cholesterol levels has implications for understanding the function of the APP and for devising anti-amyloidogenic preventive strategies in AD.

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Section: Therapeutic Implications Of Complex Formation Between C99/apmentioning

confidence: 99%

Direct binding of cholesterol to the amyloid precursor protein: An important interaction in lipid–Alzheimer's disease relationships?

Beel

Sakakura

Barrett

et al. 2010

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

154

229

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“…micelles, phospholipids vesicles, and bicelles), and in particular, the lack of exogenous probes with high affinity and specificity (1). Conventional antibody-based probing techniques are only useful for water-soluble regions of proteins.…”

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confidence: 99%

Computationally Designed Peptide Inhibitors of Protein−Protein Interactions in Membranes

Caputo

Litvinov

et al. 2008

Biochemistry

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We recently reported a computational method (CHAMP) to design sequence-specific peptides that bind to the membrane-embedded portions of transmembrane proteins. We successfully applied this method to design membrane-spanning peptides targeting the transmembrane domains of the α IIbsubunit of integrin α IIb β 3 . Previously, we demonstrated that these CHAMP peptides bind specifically with reasonable affinity to isolated transmembrane helices of the targeted transmembrane region. These peptides also induced integrin α IIb β 3 activation due to disruption of the helix-helix interactions between the transmembrane domains of the α IIb and β 3 subunits. In this paper, we show the direct interaction of the designed anti-α IIb CHAMP peptide with isolated full-length integrin α IIb β 3 in detergent micelles. Further, the behavior of the designed peptides in phospholipid bilayers is essentially identical to their behavior in detergent micelles. In particular, the peptides assume a membrane-spanning α-helical conformation that does not disrupt bilayer integrity. The activity and selectivity of the CHAMP peptides was further explored in platelets, comfirming that anti-α IIb activates wild type α IIb β 3 in whole cells as a result of its disruption of the protein-protein interactions between the α-and β-subunits at the transmembrane regions. These results demonstrate that CHAMP is a successful chemical biology approach that can provide specific tools to probe the transmembrane domains of proteins.Keywords membrane protein; protein-protein interactions; transmembrane domain; computational design; integrin Membrane proteins account for approximately 30% of the entire human proteome; however, studies of their transmembrane (TM) domains have lagged behind due to limitation of their availability, the complexity of the model systems used to study membrane proteins (e.g. micelles, phospholipids vesicles, and bicelles), and in particular, the lack of exogenous probes Computational protein engineering has made major strides (2). There are now a variety of methods to design proteins that recognize water-soluble regions of target proteins (3-6), but few companion methods for targeting TM regions have been successful. Recently, we reported a general strategy for the computational design of TM domain-targeted peptides, designated the CHAMP (computed helical anti-membrane protein) method (7). We illustrated the utility of the method by designing peptides that specifically recognize the TM helix of the α-subunit of the platelet integrin α IIb β 3 . The TM helices of the α and β subunits of integrin α IIb β 3 are thought to associate heteromerically in unstimulated platelets and to dissociate following platelet stimulation (8-10). We showed that anti-α IIb , a peptide designed to target the α IIb TM helix, activated α IIb β 3 by disrupting the heteromeric α IIb /β 3 TM helix-helix interaction of the resting integrin (Figure 1). These results illustrate the potential of CHAMP method for generating high affinity molecules that bind to ...

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“…Furthermore, pentamidine specifically inhibits EBV LMP-1 signaling. Significant progress has been made in the development of small molecule regulators of PPIs [29], [30], [31], however, the development of small molecular probes to interrogate protein transmembrane domains is still lagging behind [32], [33], [34], [35]. Herein we provide a novel non-peptide small molecule agent for regulating LMP-1 TMD-5 lateral interactions.…”

Section: Discussionmentioning

confidence: 99%

“…Compared to a peptidomimetic, a small molecule anti-TMD agent is more resistant to degradation [36]. This kind of small molecule agent is also superior to antibody-based methods, which can not be used in cellular membranes [32]. Additionally, pentamidine is an FDA approved drug since 1989, which eliminates the possibility of severe toxicology.…”

Section: Discussionmentioning

confidence: 99%

Repositioning Antimicrobial Agent Pentamidine as a Disruptor of the Lateral Interactions of Transmembrane Domain 5 of EBV Latent Membrane Protein 1

et al. 2012

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The lateral transmembrane protein-protein interactions (PPI) have been regarded as “undruggable” despite their importance in many essential biological processes. The homo-trimerization of transmembrane domain 5 (TMD-5) of latent membrane protein 1 (LMP-1) is critical for the constitutive oncogenic activation of the Epstein-Barr virus (EBV). Herein we repurpose the antimicrobial agent pentamidine as a regulator of LMP-1 TMD-5 lateral interactions. The results of ToxR assay, tryptophan fluorescence assay, courmarin fluorescence dequenching assay, and Bis-Tris sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) consistently show pentamidine disrupts LMP-1 TMD-5 lateral interactions. Furthermore, pentamidine inhibits LMP-1 signaling, inducing cellular apoptosis and suppressing cell proliferation in the EBV infected B cells. In contrast, EBV negative cells are less susceptible to pentamidine. This study provides a novel non-peptide small molecule agent for regulating LMP-1 TMD-5 lateral interactions.

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Exogenous Agents that Target Transmembrane Domains of Proteins

Cited by 20 publications

References 85 publications

Direct binding of cholesterol to the amyloid precursor protein: An important interaction in lipid–Alzheimer's disease relationships?

Direct binding of cholesterol to the amyloid precursor protein: An important interaction in lipid–Alzheimer's disease relationships?

Computationally Designed Peptide Inhibitors of Protein−Protein Interactions in Membranes

Repositioning Antimicrobial Agent Pentamidine as a Disruptor of the Lateral Interactions of Transmembrane Domain 5 of EBV Latent Membrane Protein 1

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