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Related Concept Videos

Assembly of Signaling Complexes01:30

Assembly of Signaling Complexes

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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.
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Nuclear protein sorting regulates nucleus composition and gene expression, crucial for determining the fate of a eukaryotic cell. Hence, the entry and exit of molecules across the nuclear envelope is a tightly controlled process. Nuclear protein sorting can be inhibited by one of the following ways: 1) masking cargo signal sequences, 2) modifying the nuclear receptor's affinity for cargo, 3) controlling the nuclear pore size, 4) retaining the cargo during its transit to the cytosol or the...
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The cadherins were one of the first cell adhesion molecules discovered; the term “cadherins”   is based on their calcium-dependent adhering properties. The first cadherins discovered on the epithelial, neuronal, and placental cells were named E-cadherin, P-cadherin, and N-cadherin, respectively. These classical cadherins share sequence and structural similarities. Other cadherins, including those involved in cell signaling, are grouped into non-classical cadherins. This...
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Related Experiment Video

Updated: May 29, 2025

A Flow Cytometry-based Assay to Identify Compounds That Disrupt Binding of Fluorescently-labeled CXC Chemokine Ligand 12 to CXC Chemokine Receptor 4
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Structural basis of CXCR4 assembly and regulation.

Aijun Liu1, Yezhou Liu1, Richard D Ye2

  • 1Dongguan Songshan Lake Central Hospital, Dongguan Third People's Hospital, The Affiliated Dongguan Songshan Lake Central Hospital, Guangdong Medical University, Dongguan, Guangdong 523326, China; Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong 518172, China.

Cell Reports
|February 1, 2025
PubMed
Summary

The study reveals the cryo-EM structure of a CXC chemokine receptor 4 (CXCR4) homo-tetramer, uncovering a mutually inhibitory mechanism that regulates receptor activation and self-assembly.

Keywords:
CP: Molecular biologyCXCR4CXCR4 assemblyallosteric regulationcryo-EM structuredrug discovery

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In Vitro Analysis of PDZ-dependent CFTR Macromolecular Signaling Complexes
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Area of Science:

  • Structural Biology
  • Molecular Pharmacology
  • Biochemistry

Background:

  • CXC chemokine receptor 4 (CXCR4) is a critical drug target within the chemokine receptor family.
  • Receptor assembly is vital for chemokine receptor function, but structural data on their organization is scarce.

Purpose of the Study:

  • To determine the three-dimensional structure of a CXCR4 homo-tetramer.
  • To elucidate the molecular mechanisms underlying CXCR4 self-assembly and allosteric regulation.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) was employed to resolve the structure.
  • Detailed structural analysis of the tetrameric arrangement and inter-protomer interfaces.

Main Results:

  • The first cryo-EM structure of a CXCR4 homo-tetramer exhibiting C4 rotational symmetry was determined.
  • Interactions between protomers via transmembrane helices (TM1/2 and TM5/6/7) and ECL3 loops were identified.
  • A novel allosteric and antagonistic mechanism involving specific residue interactions (Q272, K38, V99) was revealed, leading to mutual inhibition.

Conclusions:

  • The study provides a structural basis for understanding CXCR4 self-assembly and its allosteric regulation.
  • The identified mutually inhibitory mechanism prevents excessive receptor activation.
  • These findings offer insights for developing novel therapeutic strategies targeting CXCR4.