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Autoinhibition in the Signal Transducer CIN85 Modulates B Cell Activation.

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A newly discovered intramolecular interaction in CIN85 protein regulates B cell receptor signaling condensates. This finding reveals how CIN85 valency modulation impacts B cell activation and calcium mobilization.

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Area of Science:

  • Molecular Biology
  • Cellular Signaling
  • Biochemistry

Background:

  • B cell receptor (BCR) signaling relies on protein organization within phase-separated condensates.
  • Key proteins like SLP65 and CIN85 form these condensates via interactions between Src homology 3 (SH3) domains and proline-rich motifs (PRMs).
  • The precise conformational dynamics governing these condensates and their role in BCR signaling remain unclear.

Purpose of the Study:

  • To investigate the structural basis of SLP65/CIN85 condensate formation.
  • To identify novel interactions within CIN85 that regulate its function in BCR signaling.
  • To elucidate how protein conformation impacts B cell activation.

Main Methods:

  • High-resolution nuclear magnetic resonance (NMR) spectroscopy to study protein conformation.
  • Analysis of multidomain protein constructs and flexible linker regions.
  • B cell culture experiments to assess signaling dynamics.

Main Results:

  • Identified a previously unknown intramolecular interaction between CIN85's C-terminal SH3 domain (SH3C) and an adjacent PRM.
  • Demonstrated that phosphorylation of a nearby serine residue dynamically modulates this intramolecular interaction, affecting CIN85's valency.
  • Confirmed the interaction's critical role in SLP65/CIN85 condensate formation, CIN85 membrane recruitment, and calcium mobilization in B cells.

Conclusions:

  • The intramolecular SH3C:PRM interaction in CIN85 is a key regulatory mechanism.
  • This interaction dynamically controls CIN85 valency, impacting condensate formation and B cell signaling.
  • Findings provide insights into the molecular basis of BCR signal transduction regulation.