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Transducer Mechanism: Enzyme-Linked Receptors01:27

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Enzyme-linked receptors are cell-surface receptors acting as an enzyme or associating with an enzyme intracellularly. They make excellent drug targets. Drugs can bind to the extracellular ligand-binding domain or directly affect their enzymatic domain and alter their activity.
Major types that are helpful drug targets include:
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Enzyme-linked receptors are proteins that act as both receptor and enzyme, activating multiple intracellular signals. This is a large group of receptors that include the receptor tyrosine kinase (RTK) family. Many growth factors and hormones bind to and activate the RTKs.
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Transducer Mechanism: G Protein–Coupled Receptors01:30

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G Protein–Coupled Receptors (GPCRs) are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to various stimuli. GPCRs regulate critical physiological pathways and are excellent drug targets for treating diseases such as diabetes, cancer, obesity, depression, or Alzheimer's. Nearly 35% of approved drugs implement their therapeutic effects by selectively interacting with specific GPCRs.
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Signal Transduction: Overview01:26

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Cells respond to many types of information, often through receptor proteins positioned on the membrane. They respond to chemical signals, such as hormones, neurotransmitters, and other signaling molecules, initiating a series of molecular reactions to produce an appropriate response. This is called signal transduction. Cells also coordinate different responses elicited by the same signaling molecule via mediators, allowing molecular cross-talk.
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Multiprotein signaling complexes are formed in a dynamic process involving protein-protein interactions at the cytoplasmic domain of transmembrane receptors or enzymatic and non-enzymatic proteins associated with the receptor. These complexes ensure the activation and propagation of intracellular signals that regulate cell functions.
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
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When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze...
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Mimicking the Function of Signaling Proteins: Toward Artificial Signal Transduction Therapy
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An Engineered Synthetic Receptor-Aptamer Pair for an Artificial Signal Transduction System.

Hanrui Liu, Toni A Baeumler, Kai Nakamura

  • 1Research Center for Drug and Vaccine Development National Institute of Infectious Diseases, 1-23-1, Toyama, Shinjuku-ku, Tokyo, 162-8640, Japan.

ACS Nano
|May 8, 2023
PubMed
Summary

Engineered receptors can be precisely controlled using DNA aptamers for custom cellular functions. This aptamer-based system offers tunable signaling and modular sensing without genetic modification.

Keywords:
aptamerprotein−protein interactionsreceptor engineeringsignal transductionsynthetic biology

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Area of Science:

  • Synthetic biology
  • Molecular engineering
  • Cellular signaling

Background:

  • Cell membrane receptors are crucial for sensing external signals and regulating cellular functions.
  • Receptor engineering aims to direct cellular responses but faces challenges in precise signal modulation.
  • Existing methods often lack specificity and tunability in engineered receptor systems.

Purpose of the Study:

  • To develop a novel aptamer-based signal transduction system for controlling engineered receptors.
  • To enable precise modulation and customization of cellular responses to external cues.
  • To create a versatile platform for modular sensing of extracellular molecules.

Main Methods:

  • Engineered a synthetic receptor system using a membrane receptor-aptamer pair.
  • Modified the receptor's extracellular domain to ensure exclusive activation by DNA aptamers.
  • Utilized aptamer ligands with varying dimerization propensities to tune signaling output.

Main Results:

  • Demonstrated a functional synthetic receptor system activated solely by exogenous DNA aptamers.
  • Achieved tunable signaling output levels by selecting aptamers with different dimerization affinities.
  • Showcased the ability to sense diverse extracellular molecules without receptor genetic modification.

Conclusions:

  • The aptamer-based system provides a powerful tool for precise control and customization of engineered receptor functions.
  • This approach overcomes limitations in receptor cross-reactivity and allows for modular sensing applications.
  • The developed system offers significant potential for advancing synthetic biology and therapeutic applications.