Mechanisms of PDZ domain scaffold assembly illuminated by use of supported cell membrane sheets
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Mechanisms of PDZ domain scaffold assembly illuminated by use of supported cell membrane sheets. / Erlendsson, Simon; Thorsen, Thor Seneca; Vauquelin, Georges; Ammendrup-Johnsen, Ina; Wirth, Volker; Martinez, Karen L.; Teilum, Kaare; Gether, Ulrik; Madsen, Kenneth Lindegaard.
I: eLife, Bind 8, e39180, 2019, s. 1-27.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Mechanisms of PDZ domain scaffold assembly illuminated by use of supported cell membrane sheets
AU - Erlendsson, Simon
AU - Thorsen, Thor Seneca
AU - Vauquelin, Georges
AU - Ammendrup-Johnsen, Ina
AU - Wirth, Volker
AU - Martinez, Karen L.
AU - Teilum, Kaare
AU - Gether, Ulrik
AU - Madsen, Kenneth Lindegaard
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
KW - biochemistry
KW - chemical biology
KW - none
KW - post synaptic density
KW - scaffold proteins
KW - synaptic structure
U2 - 10.7554/eLife.39180
DO - 10.7554/eLife.39180
M3 - Journal article
C2 - 30605082
AN - SCOPUS:85060388425
VL - 8
SP - 1
EP - 27
JO - eLife
JF - eLife
SN - 2050-084X
M1 - e39180
ER -
ID: 215785547