Mechanisms of PDZ Domain Scaffold Assembly Illuminated by Use of Supported Cell Membrane Sheets

Overview

Journal Elife

Specialty Biology

Date 2019 Jan 4

PMID 30605082

Citations 9

Authors

Simon Erlendsson

Thor Seneca Thorsen

Georges Vauquelin

Ina Ammendrup-Johnsen

Volker Wirth

Karen L Martinez

Kaare Teilum

Ulrik Gether

Kenneth Lindegaard Madsen

Affiliations

Soon will be listed here.

Abstract

PDZ domain scaffold proteins are molecular modules orchestrating cellular signalling in space and time. Here, we investigate assembly of PDZ scaffolds using supported cell membrane sheets, a unique experimental setup enabling direct access to the intracellular face of the cell membrane. Our data demonstrate how multivalent protein-protein and protein-lipid interactions provide critical avidity for the strong binding between the PDZ domain scaffold proteins, PICK1 and PSD-95, and their cognate transmembrane binding partners. The kinetics of the binding were remarkably slow and binding strength two-three orders of magnitude higher than the intrinsic affinity for the isolated PDZ interaction. Interestingly, discrete changes in the intrinsic PICK1 PDZ affinity did not affect overall binding strength but instead revealed dual scaffold modes for PICK1. Our data supported by simulations suggest that intrinsic PDZ domain affinities are finely tuned and encode specific cellular responses, enabling multiplexed cellular functions of PDZ scaffolds.

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