Signaling mechanism of the transmembrane energy receptor Aer
- 1Cornel University
Abstract
The E. coli aerotaxis receptor Aer is a bacterial chemoreceptor that senses intracellular redox changes via an N terminal PAS domain bound to a flavin adenine dinucleotide (FAD) cofactor. Distinct from canonical methyl-accepting chemotaxis proteins (MCPs) such as Tar/Tsr, Aer lacks a periplasmic ligand-binding domain and adaptive methylation, transmitting conformational signals laterally from the PAS domain to the HAMP domain and the methylation helix-like cap (MHL cap) of the kinase control domain (KCD). To elucidate the Aer signalling mechanism, we determined cryo electron microscopy (cryo EM) structures of full length Aer in oxidized flavin quinone (kinase on) and reduced semiquinone (kinase off) states. Structural comparison reveals redox linked rearrangements of the FAD binding pocket, reorientation of PAS-HAMP interactions, and strikingly altered MHL cap stability. PAS-MHL-cap contact in the oxidized state compresses the receptor and stabilized proximal KCD helices, whereas reduction disrupts these contacts, increasing KCD flexibility. To probe distal effects on KCD architecture, we performed nanodisc reconstitution and pulse dipolar ESR spectroscopy on spin labelled positions along the four helix bundle. Distance distributions indicate redox dependent changes in helix separation, particularly at the C terminal MHL2 region, consistent with PAS driven loosening of KCD packing in kinase off states. These data support a model in which FAD redox chemistry reorganizes flavin pocket residues that in turn subtly alter PAS conformation to influence PAS-HAMP and PAS-MHL-cap packing and hence KCD conformational stability. The findings reveal an Aer specific signaling axis distinct from periplasmic ligand binding MCPs that has adapted MCP architecture for lateral PAS input and cytoplasmic redox sensing.
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BibTeX
@misc{olsthoorn2026signaling,
title = {{Signaling mechanism of the transmembrane energy receptor Aer}},
author = {F. A. Olsthoorn and A. R. Muok and Z. A. Maschmann and Y. Xu and S. Chandrasekaran and R. Dunleavy and B. R. CRANE},
howpublished = {bioRxiv},
year = {2026},
month = may,
doi = {10.64898/2026.05.25.727702},
url = {https://www.biorxiv.org/content/10.64898/2026.05.25.727702v2},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Signaling mechanism of the transmembrane energy receptor Aer
AU - F. A. Olsthoorn
AU - A. R. Muok
AU - Z. A. Maschmann
AU - Y. Xu
AU - S. Chandrasekaran
AU - R. Dunleavy
AU - B. R. CRANE
PY - 2026
DA - 2026/05/25
PB - bioRxiv
DO - 10.64898/2026.05.25.727702
UR - https://www.biorxiv.org/content/10.64898/2026.05.25.727702v2
AB - The E. coli aerotaxis receptor Aer is a bacterial chemoreceptor that senses intracellular redox changes via an N terminal PAS domain bound to a flavin adenine dinucleotide (FAD) cofactor. Distinct from canonical methyl-accepting chemotaxis proteins (MCPs) such as Tar/Tsr, Aer lacks a periplasmic ligand-binding domain and adaptive methylation, transmitting conformational signals laterally from the PAS domain to the HAMP domain and the methylation helix-like cap (MHL cap) of the kinase control domain (KCD). To elucidate the Aer signalling mechanism, we determined cryo electron microscopy (cryo EM) structures of full length Aer in oxidized flavin quinone (kinase on) and reduced semiquinone (kinase off) states. Structural comparison reveals redox linked rearrangements of the FAD binding pocket, reorientation of PAS-HAMP interactions, and strikingly altered MHL cap stability. PAS-MHL-cap contact in the oxidized state compresses the receptor and stabilized proximal KCD helices, whereas reduction disrupts these contacts, increasing KCD flexibility. To probe distal effects on KCD architecture, we performed nanodisc reconstitution and pulse dipolar ESR spectroscopy on spin labelled positions along the four helix bundle. Distance distributions indicate redox dependent changes in helix separation, particularly at the C terminal MHL2 region, consistent with PAS driven loosening of KCD packing in kinase off states. These data support a model in which FAD redox chemistry reorganizes flavin pocket residues that in turn subtly alter PAS conformation to influence PAS-HAMP and PAS-MHL-cap packing and hence KCD conformational stability. The findings reveal an Aer specific signaling axis distinct from periplasmic ligand binding MCPs that has adapted MCP architecture for lateral PAS input and cytoplasmic redox sensing.
ER -