The intracellular lipid-binding domain of human Na+/H+ exchanger 1 forms a lipid-protein co-structure essential for activity

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Standard

The intracellular lipid-binding domain of human Na+/H+ exchanger 1 forms a lipid-protein co-structure essential for activity. / Hendus-Altenburger, Ruth; Vogensen, Jens; Pedersen, Emilie Skotte; Luchini, Alessandra; Araya-Secchi, Raul; Bendsoe, Anne H.; Prasad, Nanditha Shyam; Prestel, Andreas; Cardenas, Marite; Pedraz-Cuesta, Elena; Arleth, Lise; Pedersen, Stine Helene Falsig; Kragelund, Birthe B.

I: Communications Biology , Bind 3, Nr. 1, 731, 03.12.2020.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Harvard

Hendus-Altenburger, R, Vogensen, J, Pedersen, ES, Luchini, A, Araya-Secchi, R, Bendsoe, AH, Prasad, NS, Prestel, A, Cardenas, M, Pedraz-Cuesta, E, Arleth, L, Pedersen, SHF & Kragelund, BB 2020, 'The intracellular lipid-binding domain of human Na+/H+ exchanger 1 forms a lipid-protein co-structure essential for activity', Communications Biology , bind 3, nr. 1, 731. https://doi.org/10.1038/s42003-020-01455-6

APA

Hendus-Altenburger, R., Vogensen, J., Pedersen, E. S., Luchini, A., Araya-Secchi, R., Bendsoe, A. H., Prasad, N. S., Prestel, A., Cardenas, M., Pedraz-Cuesta, E., Arleth, L., Pedersen, S. H. F., & Kragelund, B. B. (2020). The intracellular lipid-binding domain of human Na+/H+ exchanger 1 forms a lipid-protein co-structure essential for activity. Communications Biology , 3(1), [731]. https://doi.org/10.1038/s42003-020-01455-6

Vancouver

Hendus-Altenburger R, Vogensen J, Pedersen ES, Luchini A, Araya-Secchi R, Bendsoe AH o.a. The intracellular lipid-binding domain of human Na+/H+ exchanger 1 forms a lipid-protein co-structure essential for activity. Communications Biology . 2020 dec. 3;3(1). 731. https://doi.org/10.1038/s42003-020-01455-6

Author

Hendus-Altenburger, Ruth ; Vogensen, Jens ; Pedersen, Emilie Skotte ; Luchini, Alessandra ; Araya-Secchi, Raul ; Bendsoe, Anne H. ; Prasad, Nanditha Shyam ; Prestel, Andreas ; Cardenas, Marite ; Pedraz-Cuesta, Elena ; Arleth, Lise ; Pedersen, Stine Helene Falsig ; Kragelund, Birthe B. / The intracellular lipid-binding domain of human Na+/H+ exchanger 1 forms a lipid-protein co-structure essential for activity. I: Communications Biology . 2020 ; Bind 3, Nr. 1.

Bibtex

@article{bcdaae232d90468fb1db557bde887799,
title = "The intracellular lipid-binding domain of human Na+/H+ exchanger 1 forms a lipid-protein co-structure essential for activity",
abstract = "Dynamic interactions of proteins with lipid membranes are essential regulatory events in biology, but remain rudimentarily understood and particularly overlooked in membrane proteins. The ubiquitously expressed membrane protein Na+/H+-exchanger 1 (NHE1) regulates intracellular pH (pH(i)) with dysregulation linked to e.g. cancer and cardiovascular diseases. NHE1 has a long, regulatory cytosolic domain carrying a membrane-proximal region described as a lipid-interacting domain (LID), yet, the LID structure and underlying molecular mechanisms are unknown. Here we decompose these, combining structural and biophysical methods, molecular dynamics simulations, cellular biotinylation- and immunofluorescence analysis and exchanger activity assays. We find that the NHE1-LID is intrinsically disordered and, in presence of membrane mimetics, forms a helical alpha alpha -hairpin co-structure with the membrane, anchoring the regulatory domain vis-a-vis the transport domain. This co-structure is fundamental for NHE1 activity, as its disintegration reduced steady-state pH(i) and the rate of pH(i) recovery after acid loading. We propose that regulatory lipid-protein co-structures may play equally important roles in other membrane proteins. Hendus-Altenburger et al. provide biochemical, structural and functional information on the lipid interaction domain (LID) of the Na+/H+ Exchanger 1 (NHE1). They find that NHE1-LID is intrinsically disordered, but, when allowed to interact with a lipid membrane, forms a helical alpha alpha -hairpin, stabilized by hydrophobic and electrostatic interactions. This co-structure is fundamental for NHE1 activity, giving insight into membrane protein regulation via disordered domains.",
keywords = "PHOSPHOINOSITIDE BINDING, PHOSPHOLIPID-BINDING, CYTOPLASMIC DOMAINS, ESSENTIAL COFACTOR, NMR-SPECTROSCOPY, MEMBRANE-BINDING, NHE1, PH, ALPHA, ACTIVATION",
author = "Ruth Hendus-Altenburger and Jens Vogensen and Pedersen, {Emilie Skotte} and Alessandra Luchini and Raul Araya-Secchi and Bendsoe, {Anne H.} and Prasad, {Nanditha Shyam} and Andreas Prestel and Marite Cardenas and Elena Pedraz-Cuesta and Lise Arleth and Pedersen, {Stine Helene Falsig} and Kragelund, {Birthe B.}",
year = "2020",
month = dec,
day = "3",
doi = "10.1038/s42003-020-01455-6",
language = "English",
volume = "3",
journal = "Communications Biology",
issn = "2399-3642",
publisher = "nature publishing group",
number = "1",

}

RIS

TY - JOUR

T1 - The intracellular lipid-binding domain of human Na+/H+ exchanger 1 forms a lipid-protein co-structure essential for activity

AU - Hendus-Altenburger, Ruth

AU - Vogensen, Jens

AU - Pedersen, Emilie Skotte

AU - Luchini, Alessandra

AU - Araya-Secchi, Raul

AU - Bendsoe, Anne H.

AU - Prasad, Nanditha Shyam

AU - Prestel, Andreas

AU - Cardenas, Marite

AU - Pedraz-Cuesta, Elena

AU - Arleth, Lise

AU - Pedersen, Stine Helene Falsig

AU - Kragelund, Birthe B.

PY - 2020/12/3

Y1 - 2020/12/3

N2 - Dynamic interactions of proteins with lipid membranes are essential regulatory events in biology, but remain rudimentarily understood and particularly overlooked in membrane proteins. The ubiquitously expressed membrane protein Na+/H+-exchanger 1 (NHE1) regulates intracellular pH (pH(i)) with dysregulation linked to e.g. cancer and cardiovascular diseases. NHE1 has a long, regulatory cytosolic domain carrying a membrane-proximal region described as a lipid-interacting domain (LID), yet, the LID structure and underlying molecular mechanisms are unknown. Here we decompose these, combining structural and biophysical methods, molecular dynamics simulations, cellular biotinylation- and immunofluorescence analysis and exchanger activity assays. We find that the NHE1-LID is intrinsically disordered and, in presence of membrane mimetics, forms a helical alpha alpha -hairpin co-structure with the membrane, anchoring the regulatory domain vis-a-vis the transport domain. This co-structure is fundamental for NHE1 activity, as its disintegration reduced steady-state pH(i) and the rate of pH(i) recovery after acid loading. We propose that regulatory lipid-protein co-structures may play equally important roles in other membrane proteins. Hendus-Altenburger et al. provide biochemical, structural and functional information on the lipid interaction domain (LID) of the Na+/H+ Exchanger 1 (NHE1). They find that NHE1-LID is intrinsically disordered, but, when allowed to interact with a lipid membrane, forms a helical alpha alpha -hairpin, stabilized by hydrophobic and electrostatic interactions. This co-structure is fundamental for NHE1 activity, giving insight into membrane protein regulation via disordered domains.

AB - Dynamic interactions of proteins with lipid membranes are essential regulatory events in biology, but remain rudimentarily understood and particularly overlooked in membrane proteins. The ubiquitously expressed membrane protein Na+/H+-exchanger 1 (NHE1) regulates intracellular pH (pH(i)) with dysregulation linked to e.g. cancer and cardiovascular diseases. NHE1 has a long, regulatory cytosolic domain carrying a membrane-proximal region described as a lipid-interacting domain (LID), yet, the LID structure and underlying molecular mechanisms are unknown. Here we decompose these, combining structural and biophysical methods, molecular dynamics simulations, cellular biotinylation- and immunofluorescence analysis and exchanger activity assays. We find that the NHE1-LID is intrinsically disordered and, in presence of membrane mimetics, forms a helical alpha alpha -hairpin co-structure with the membrane, anchoring the regulatory domain vis-a-vis the transport domain. This co-structure is fundamental for NHE1 activity, as its disintegration reduced steady-state pH(i) and the rate of pH(i) recovery after acid loading. We propose that regulatory lipid-protein co-structures may play equally important roles in other membrane proteins. Hendus-Altenburger et al. provide biochemical, structural and functional information on the lipid interaction domain (LID) of the Na+/H+ Exchanger 1 (NHE1). They find that NHE1-LID is intrinsically disordered, but, when allowed to interact with a lipid membrane, forms a helical alpha alpha -hairpin, stabilized by hydrophobic and electrostatic interactions. This co-structure is fundamental for NHE1 activity, giving insight into membrane protein regulation via disordered domains.

KW - PHOSPHOINOSITIDE BINDING

KW - PHOSPHOLIPID-BINDING

KW - CYTOPLASMIC DOMAINS

KW - ESSENTIAL COFACTOR

KW - NMR-SPECTROSCOPY

KW - MEMBRANE-BINDING

KW - NHE1

KW - PH

KW - ALPHA

KW - ACTIVATION

U2 - 10.1038/s42003-020-01455-6

DO - 10.1038/s42003-020-01455-6

M3 - Journal article

C2 - 33273619

VL - 3

JO - Communications Biology

JF - Communications Biology

SN - 2399-3642

IS - 1

M1 - 731

ER -

ID: 254462352