The citron homology domain as a scaffold for Rho1 signaling

Sergio G. Bartual; Wenfan Wei; Yao Zhou; Veronica M. Pravata; Wenxia Fang; Kaizhou Yan; Andrew T. Ferenbach; Deborah E. A. Lockhart; Daan M. F. van Aalten

doi:10.1073/pnas.2110298118

The citron homology domain as a scaffold for Rho1 signaling

Sergio G. Bartual, Wenfan Wei, Yao Zhou, Veronica M. Pravata, Wenxia Fang, Kaizhou Yan, Andrew T. Ferenbach, Deborah E. A. Lockhart, Daan M. F. van Aalten (Lead / Corresponding author)

Molecular Microbiology

Research output: Contribution to journal › Article › peer-review

8 Citations (Scopus)

68 Downloads (Pure)

Abstract

Aspergillus fumigatus is a human opportunistic pathogen showing emerging resistance against a limited repertoire of antifungal agents available. The GTPase Rho1 has been identified as an important regulator of the cell wall integrity signaling pathway that regulates the composition of the cell wall, a structure that is unique to fungi and serves as a target for antifungal compounds. Rom2, the guanine nucleotide exchange factor to Rho1, contains a C-terminal citron homology (CNH) domain of unknown function that is found in many other eukaryotic genes. Here, we show that the Rom2 CNH domain interacts directly with Rho1 to modulate β-glucan and chitin synthesis. We report the structure of the Rom2 CNH domain, revealing that it adopts a seven-bladed β-propeller fold containing three unusual loops. A model of the Rho1-Rom2 CNH complex suggests that the Rom2 CNH domain interacts with the Rho1 Switch II motif. This work uncovers the role of the Rom2 CNH domain as a scaffold for Rho1 signaling in fungal cell wall biosynthesis.

Original language	English
Article number	e2110298118
Number of pages	10
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	118
Issue number	39
Early online date	20 Sept 2021
DOIs	https://doi.org/10.1073/pnas.2110298118
Publication status	Published - 28 Sept 2021

Keywords

Aspergillus fumigatus
cell wall
Rom2
CNH domain
AfRho1
protein-protein interaction
Signal transduction
Citron homology domain
Cell wall
Structural biology

ASJC Scopus subject areas

General

Access to Document

10.1073/pnas.2110298118Licence: CC BY

Final Published VersionFinal published version, 1.36 MBLicence: CC BY

Cite this

@article{3dcfe02270c0464d9d940f05e2dee022,

title = "The citron homology domain as a scaffold for Rho1 signaling",

abstract = "Aspergillus fumigatus is a human opportunistic pathogen showing emerging resistance against a limited repertoire of antifungal agents available. The GTPase Rho1 has been identified as an important regulator of the cell wall integrity signaling pathway that regulates the composition of the cell wall, a structure that is unique to fungi and serves as a target for antifungal compounds. Rom2, the guanine nucleotide exchange factor to Rho1, contains a C-terminal citron homology (CNH) domain of unknown function that is found in many other eukaryotic genes. Here, we show that the Rom2 CNH domain interacts directly with Rho1 to modulate β-glucan and chitin synthesis. We report the structure of the Rom2 CNH domain, revealing that it adopts a seven-bladed β-propeller fold containing three unusual loops. A model of the Rho1-Rom2 CNH complex suggests that the Rom2 CNH domain interacts with the Rho1 Switch II motif. This work uncovers the role of the Rom2 CNH domain as a scaffold for Rho1 signaling in fungal cell wall biosynthesis.",

keywords = "Aspergillus fumigatus, cell wall, Rom2, CNH domain, AfRho1, protein-protein interaction, Signal transduction, Citron homology domain, Cell wall, Structural biology",

author = "Bartual, {Sergio G.} and Wenfan Wei and Yao Zhou and Pravata, {Veronica M.} and Wenxia Fang and Kaizhou Yan and Ferenbach, {Andrew T.} and Lockhart, {Deborah E. A.} and {van Aalten}, {Daan M. F.}",

note = "This work was funded by an MRC Programme Grant (V001094) to D.M.F.v.A.; W.W. was supported by the Chinese Scholarship Council and D.E.A.L. by a Wellcome Trust Postdoctoral Research Training Fellowship for Clinicians (WT105772).",

year = "2021",

month = sep,

day = "28",

doi = "10.1073/pnas.2110298118",

language = "English",

volume = "118",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Academy of Sciences",

number = "39",

}

TY - JOUR

T1 - The citron homology domain as a scaffold for Rho1 signaling

AU - Bartual, Sergio G.

AU - Wei, Wenfan

AU - Zhou, Yao

AU - Pravata, Veronica M.

AU - Fang, Wenxia

AU - Yan, Kaizhou

AU - Ferenbach, Andrew T.

AU - Lockhart, Deborah E. A.

AU - van Aalten, Daan M. F.

N1 - This work was funded by an MRC Programme Grant (V001094) to D.M.F.v.A.; W.W. was supported by the Chinese Scholarship Council and D.E.A.L. by a Wellcome Trust Postdoctoral Research Training Fellowship for Clinicians (WT105772).

PY - 2021/9/28

Y1 - 2021/9/28

N2 - Aspergillus fumigatus is a human opportunistic pathogen showing emerging resistance against a limited repertoire of antifungal agents available. The GTPase Rho1 has been identified as an important regulator of the cell wall integrity signaling pathway that regulates the composition of the cell wall, a structure that is unique to fungi and serves as a target for antifungal compounds. Rom2, the guanine nucleotide exchange factor to Rho1, contains a C-terminal citron homology (CNH) domain of unknown function that is found in many other eukaryotic genes. Here, we show that the Rom2 CNH domain interacts directly with Rho1 to modulate β-glucan and chitin synthesis. We report the structure of the Rom2 CNH domain, revealing that it adopts a seven-bladed β-propeller fold containing three unusual loops. A model of the Rho1-Rom2 CNH complex suggests that the Rom2 CNH domain interacts with the Rho1 Switch II motif. This work uncovers the role of the Rom2 CNH domain as a scaffold for Rho1 signaling in fungal cell wall biosynthesis.

AB - Aspergillus fumigatus is a human opportunistic pathogen showing emerging resistance against a limited repertoire of antifungal agents available. The GTPase Rho1 has been identified as an important regulator of the cell wall integrity signaling pathway that regulates the composition of the cell wall, a structure that is unique to fungi and serves as a target for antifungal compounds. Rom2, the guanine nucleotide exchange factor to Rho1, contains a C-terminal citron homology (CNH) domain of unknown function that is found in many other eukaryotic genes. Here, we show that the Rom2 CNH domain interacts directly with Rho1 to modulate β-glucan and chitin synthesis. We report the structure of the Rom2 CNH domain, revealing that it adopts a seven-bladed β-propeller fold containing three unusual loops. A model of the Rho1-Rom2 CNH complex suggests that the Rom2 CNH domain interacts with the Rho1 Switch II motif. This work uncovers the role of the Rom2 CNH domain as a scaffold for Rho1 signaling in fungal cell wall biosynthesis.

KW - Aspergillus fumigatus

KW - cell wall

KW - Rom2

KW - CNH domain

KW - AfRho1

KW - protein-protein interaction

KW - Signal transduction

KW - Citron homology domain

KW - Cell wall

KW - Structural biology

UR - http://www.scopus.com/inward/record.url?scp=85115304467&partnerID=8YFLogxK

U2 - 10.1073/pnas.2110298118

DO - 10.1073/pnas.2110298118

M3 - Article

C2 - 34544876

SN - 0027-8424

VL - 118

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 39

M1 - e2110298118

ER -

The citron homology domain as a scaffold for Rho1 signaling

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Chemical and Genetic Validation of Aspergillus Fumigatus Cell Wall Targets

Inhibition by Proxy Targeting Fungal Citin Synthesis through Sugar Nucleotide Biosynthesis (Clinical Postdoctoral Research Training Fellowship)

Dundee Imaging Facility

Fingerprints Proteomics Facility

Cite this

The citron homology domain as a scaffold for Rho1 signaling

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Projects

Chemical and Genetic Validation of Aspergillus Fumigatus Cell Wall Targets

Inhibition by Proxy Targeting Fungal Citin Synthesis through Sugar Nucleotide Biosynthesis (Clinical Postdoctoral Research Training Fellowship)

Equipment

Dundee Imaging Facility

Fingerprints Proteomics Facility

Cite this