Functional anatomy of an allosteric protein

Prasad Purohit, Shaweta Gupta, Snehal Jadey, Anthony Auerbach

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Synaptic receptors are allosteric proteins that switch on and off to regulate cell signalling. Here, we use single-channel electrophysiology to measure and map energy changes in the gating conformational change of a nicotinic acetylcholine receptor. Two separated regions in the α-subunits-the transmitter-binding sites and αM2-αM3 linkers in the membrane domain-have the highest values (change conformation the earliest), followed by the extracellular domain, most of the membrane domain and the gate. Large gating-energy changes occur at the transmitter-binding sites, α-subunit interfaces, the αM1 helix and the gate. We hypothesize that rearrangements of the linkers trigger the global allosteric transition, and that the hydrophobic gate unlocks in three steps. The mostly local character of side-chain energy changes and the similarly high values of separated domains, both with and without ligands, suggest that gating is not strictly a mechanical process initiated by the affinity change for the agonist.

Original languageEnglish (US)
Article number2984
JournalNature communications
Volume4
DOIs
StatePublished - Dec 19 2013

Fingerprint

anatomy
Transmitters
Anatomy
Mechanical Phenomena
Binding Sites
Cell signaling
Electrophysiology
proteins
Membranes
Neurotransmitter Receptor
Nicotinic Receptors
transmitters
Conformations
Proteins
Switches
electrophysiology
acetylcholine
Ligands
membranes
helices

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

Purohit, Prasad ; Gupta, Shaweta ; Jadey, Snehal ; Auerbach, Anthony. / Functional anatomy of an allosteric protein. In: Nature communications. 2013 ; Vol. 4.
@article{af9df557ba9740ccbc50606e66e4cecf,
title = "Functional anatomy of an allosteric protein",
abstract = "Synaptic receptors are allosteric proteins that switch on and off to regulate cell signalling. Here, we use single-channel electrophysiology to measure and map energy changes in the gating conformational change of a nicotinic acetylcholine receptor. Two separated regions in the α-subunits-the transmitter-binding sites and αM2-αM3 linkers in the membrane domain-have the highest values (change conformation the earliest), followed by the extracellular domain, most of the membrane domain and the gate. Large gating-energy changes occur at the transmitter-binding sites, α-subunit interfaces, the αM1 helix and the gate. We hypothesize that rearrangements of the linkers trigger the global allosteric transition, and that the hydrophobic gate unlocks in three steps. The mostly local character of side-chain energy changes and the similarly high values of separated domains, both with and without ligands, suggest that gating is not strictly a mechanical process initiated by the affinity change for the agonist.",
author = "Prasad Purohit and Shaweta Gupta and Snehal Jadey and Anthony Auerbach",
year = "2013",
month = "12",
day = "19",
doi = "10.1038/ncomms3984",
language = "English (US)",
volume = "4",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",

}

Functional anatomy of an allosteric protein. / Purohit, Prasad; Gupta, Shaweta; Jadey, Snehal; Auerbach, Anthony.

In: Nature communications, Vol. 4, 2984, 19.12.2013.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Functional anatomy of an allosteric protein

AU - Purohit, Prasad

AU - Gupta, Shaweta

AU - Jadey, Snehal

AU - Auerbach, Anthony

PY - 2013/12/19

Y1 - 2013/12/19

N2 - Synaptic receptors are allosteric proteins that switch on and off to regulate cell signalling. Here, we use single-channel electrophysiology to measure and map energy changes in the gating conformational change of a nicotinic acetylcholine receptor. Two separated regions in the α-subunits-the transmitter-binding sites and αM2-αM3 linkers in the membrane domain-have the highest values (change conformation the earliest), followed by the extracellular domain, most of the membrane domain and the gate. Large gating-energy changes occur at the transmitter-binding sites, α-subunit interfaces, the αM1 helix and the gate. We hypothesize that rearrangements of the linkers trigger the global allosteric transition, and that the hydrophobic gate unlocks in three steps. The mostly local character of side-chain energy changes and the similarly high values of separated domains, both with and without ligands, suggest that gating is not strictly a mechanical process initiated by the affinity change for the agonist.

AB - Synaptic receptors are allosteric proteins that switch on and off to regulate cell signalling. Here, we use single-channel electrophysiology to measure and map energy changes in the gating conformational change of a nicotinic acetylcholine receptor. Two separated regions in the α-subunits-the transmitter-binding sites and αM2-αM3 linkers in the membrane domain-have the highest values (change conformation the earliest), followed by the extracellular domain, most of the membrane domain and the gate. Large gating-energy changes occur at the transmitter-binding sites, α-subunit interfaces, the αM1 helix and the gate. We hypothesize that rearrangements of the linkers trigger the global allosteric transition, and that the hydrophobic gate unlocks in three steps. The mostly local character of side-chain energy changes and the similarly high values of separated domains, both with and without ligands, suggest that gating is not strictly a mechanical process initiated by the affinity change for the agonist.

UR - http://www.scopus.com/inward/record.url?scp=84890958919&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84890958919&partnerID=8YFLogxK

U2 - 10.1038/ncomms3984

DO - 10.1038/ncomms3984

M3 - Article

VL - 4

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 2984

ER -