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Modulation of transmembrane domain interactions in neu receptor tyrosine kinase by membrane fluidity and cholesterol
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Hasan, Muhammad, Patel, Dharmesh, Ellis, Natalie, Brown, Steven P., Lewandowski, Józef R. and Dixon, Ann M. (2019) Modulation of transmembrane domain interactions in neu receptor tyrosine kinase by membrane fluidity and cholesterol. Journal of Membrane Biology, 252 . pp. 357-369. doi:10.1007/s00232-019-00075-4 ISSN 0022-2631.
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WRAP-modulation-transmembrance-domain-neu-tyrosine-membrane-fluidity-cholesterol-2019.pdf - Accepted Version - Requires a PDF viewer. Download (687Kb) | Preview |
Official URL: http://dx.doi.org/10.1007/s00232-019-00075-4
Abstract
The activation mechanism of the ErbB family of receptors is of considerable medical interest as they are linked to a number of human cancers, including an aggressive form of breast cancer. In the rat analogue of the human ErbB2 receptor, referred to as Neu, a point mutation in the transmembrane domain (V664E) has been shown to trigger oncogenic transformation. While the structural impact of this mutation has been widely studied in the past to yield models for the active state of the Neu receptor, little is known about the impact of cholesterol on its structure. Given previous reports of the influence of cholesterol on other receptor tyrosine kinases (RTKs), as well as the modulation of lipid composition in cancer cells, we wished to investigate how cholesterol content impacts the structure of the Neu transmembrane domain. We utilized high-resolution magic angle spinning solid-state NMR to measure 13C–13C coupling of selectively labelled probe residues in the Neu transmembrane domain in lipid bilayers containing cholesterol. We observe inter-helical coupling between residues that support helix–helix interactions on both dimerization motifs reported in the literature (A661-XXX-G665 and I659-XXX-V663). We further explore how changes in cholesterol concentration alter transmembrane domain interactions and the properties and mechanics of the bilayer. We interpret our results in light of previous studies relating RTK activity to cholesterol enrichment and/or depletion, and propose a novel model to explain our data that includes the recognition and binding of cholesterol by the Neu transmembrane domain through a putative cholesterol-recognition/interaction amino acid consensus sequence.
| Item Type: | Journal Article | ||||||||||||
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| Subjects: | Q Science > QC Physics Q Science > QH Natural history Q Science > QP Physiology R Medicine > RC Internal medicine |
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| Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry Faculty of Science, Engineering and Medicine > Science > Physics |
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| Library of Congress Subject Headings (LCSH): | Oncogenes , Protein-tyrosine kinase , Protein-tyrosine kinase -- Receptors, Cholesterol, Nuclear magnetic resonance , Solid state physics, Membranes (Biology) | ||||||||||||
| Journal or Publication Title: | Journal of Membrane Biology | ||||||||||||
| Publisher: | Springer | ||||||||||||
| ISSN: | 0022-2631 | ||||||||||||
| Official Date: | October 2019 | ||||||||||||
| Dates: |
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| Volume: | 252 | ||||||||||||
| Page Range: | pp. 357-369 | ||||||||||||
| DOI: | 10.1007/s00232-019-00075-4 | ||||||||||||
| Status: | Peer Reviewed | ||||||||||||
| Publication Status: | Published | ||||||||||||
| Access rights to Published version: | Restricted or Subscription Access | ||||||||||||
| Date of first compliant deposit: | 27 June 2019 | ||||||||||||
| Date of first compliant Open Access: | 20 June 2020 | ||||||||||||
| RIOXX Funder/Project Grant: |
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