RAS G-domains allosterically contribute to the recognition of lipid headgroups and acyl chains
Mutant RAS are major contributors to cancer and signal primarily from nanoclusters on the plasma membrane (PM). Their C-terminal membrane anchors are main features of membrane association. However, the same RAS isoform bound to different guanine nucleotides spatially segregate. Different RAS nanoclu...
| Main Authors: | , , , , |
|---|---|
| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2024
|
| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/175601 |
| _version_ | 1811685689050267648 |
|---|---|
| author | Arora, Neha Mu, Huanwen Liang, Hong Zhao, Wenting Zhou, Yong |
| author2 | School of Chemistry, Chemical Engineering and Biotechnology |
| author_facet | School of Chemistry, Chemical Engineering and Biotechnology Arora, Neha Mu, Huanwen Liang, Hong Zhao, Wenting Zhou, Yong |
| author_sort | Arora, Neha |
| collection | NTU |
| description | Mutant RAS are major contributors to cancer and signal primarily from nanoclusters on the plasma membrane (PM). Their C-terminal membrane anchors are main features of membrane association. However, the same RAS isoform bound to different guanine nucleotides spatially segregate. Different RAS nanoclusters all enrich a phospholipid, phosphatidylserine (PS). These findings suggest more complex membrane interactions. Our electron microscopy-spatial analysis shows that wild-types, G12V mutants, and membrane anchors of isoforms HRAS, KRAS4A, and KRAS4B prefer distinct PS species. Mechanistically, reorientation of KRAS4B G-domain exposes distinct residues, such as Arg 135 in orientation state 1 (OS1) and Arg 73/Arg 102 in OS2, to the PM and differentially facilitates the recognition of PS acyl chains. Allele-specific oncogenic mutations of KRAS4B also shift G-domain reorientation equilibrium. Indeed, KRAS4BG12V, KRAS4BG12D, KRAS4BG12C, KRAS4BG13D, and KRAS4BQ61H associate with PM lipids with headgroup and acyl chain specificities. Distribution of these KRAS4B oncogenic mutants favors different nanoscale membrane topography. Thus, RAS G-domains allosterically facilitate membrane lateral distribution. |
| first_indexed | 2024-10-01T04:48:31Z |
| format | Journal Article |
| id | ntu-10356/175601 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T04:48:31Z |
| publishDate | 2024 |
| record_format | dspace |
| spelling | ntu-10356/1756012024-05-03T15:31:49Z RAS G-domains allosterically contribute to the recognition of lipid headgroups and acyl chains Arora, Neha Mu, Huanwen Liang, Hong Zhao, Wenting Zhou, Yong School of Chemistry, Chemical Engineering and Biotechnology Institute for Digital Molecular Analytics and Science Medicine, Health and Life Sciences Rat sarcoma virus Lipid headgroups Mutant RAS are major contributors to cancer and signal primarily from nanoclusters on the plasma membrane (PM). Their C-terminal membrane anchors are main features of membrane association. However, the same RAS isoform bound to different guanine nucleotides spatially segregate. Different RAS nanoclusters all enrich a phospholipid, phosphatidylserine (PS). These findings suggest more complex membrane interactions. Our electron microscopy-spatial analysis shows that wild-types, G12V mutants, and membrane anchors of isoforms HRAS, KRAS4A, and KRAS4B prefer distinct PS species. Mechanistically, reorientation of KRAS4B G-domain exposes distinct residues, such as Arg 135 in orientation state 1 (OS1) and Arg 73/Arg 102 in OS2, to the PM and differentially facilitates the recognition of PS acyl chains. Allele-specific oncogenic mutations of KRAS4B also shift G-domain reorientation equilibrium. Indeed, KRAS4BG12V, KRAS4BG12D, KRAS4BG12C, KRAS4BG13D, and KRAS4BQ61H associate with PM lipids with headgroup and acyl chain specificities. Distribution of these KRAS4B oncogenic mutants favors different nanoscale membrane topography. Thus, RAS G-domains allosterically facilitate membrane lateral distribution. Ministry of Education (MOE) Nanyang Technological University Published version This work was supported in part by the National Institutes of Health R01GM138668 to N. Arora and Y. Zhou, Ministry of Education of Singapore (RG112/20), the Institute for Digital Molecular Analytics and Science, and the Nanyang Technological University start-up grant to W. Zhao. 2024-04-30T05:20:43Z 2024-04-30T05:20:43Z 2024 Journal Article Arora, N., Mu, H., Liang, H., Zhao, W. & Zhou, Y. (2024). RAS G-domains allosterically contribute to the recognition of lipid headgroups and acyl chains. Journal of Cell Biology, 223(5), e202307121-. https://dx.doi.org/10.1083/jcb.202307121 0021-9525 https://hdl.handle.net/10356/175601 10.1083/jcb.202307121 38334958 2-s2.0-85184719550 5 223 e202307121 en RG112/20 Journal of Cell Biology © 2024 Arora et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). application/pdf |
| spellingShingle | Medicine, Health and Life Sciences Rat sarcoma virus Lipid headgroups Arora, Neha Mu, Huanwen Liang, Hong Zhao, Wenting Zhou, Yong RAS G-domains allosterically contribute to the recognition of lipid headgroups and acyl chains |
| title | RAS G-domains allosterically contribute to the recognition of lipid headgroups and acyl chains |
| title_full | RAS G-domains allosterically contribute to the recognition of lipid headgroups and acyl chains |
| title_fullStr | RAS G-domains allosterically contribute to the recognition of lipid headgroups and acyl chains |
| title_full_unstemmed | RAS G-domains allosterically contribute to the recognition of lipid headgroups and acyl chains |
| title_short | RAS G-domains allosterically contribute to the recognition of lipid headgroups and acyl chains |
| title_sort | ras g domains allosterically contribute to the recognition of lipid headgroups and acyl chains |
| topic | Medicine, Health and Life Sciences Rat sarcoma virus Lipid headgroups |
| url | https://hdl.handle.net/10356/175601 |
| work_keys_str_mv | AT aroraneha rasgdomainsallostericallycontributetotherecognitionoflipidheadgroupsandacylchains AT muhuanwen rasgdomainsallostericallycontributetotherecognitionoflipidheadgroupsandacylchains AT lianghong rasgdomainsallostericallycontributetotherecognitionoflipidheadgroupsandacylchains AT zhaowenting rasgdomainsallostericallycontributetotherecognitionoflipidheadgroupsandacylchains AT zhouyong rasgdomainsallostericallycontributetotherecognitionoflipidheadgroupsandacylchains |