Native structure of the RhopH complex, a key determinant of malaria parasite nutrient acquisition.
cryo-EM
endogenous structural proteomics
malaria
trafficking
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
31 08 2021
31 08 2021
Historique:
entrez:
27
8
2021
pubmed:
28
8
2021
medline:
15
12
2021
Statut:
ppublish
Résumé
The RhopH complex is implicated in malaria parasites' ability to invade and create new permeability pathways in host erythrocytes, but its mechanisms remain poorly understood. Here, we enrich the endogenous RhopH complex in a native soluble form, comprising RhopH2, CLAG3.1, and RhopH3, directly from parasite cell lysates and determine its atomic structure using cryo-electron microscopy (cryo-EM), mass spectrometry, and the cryoID program. CLAG3.1 is positioned between RhopH2 and RhopH3, which both share substantial binding interfaces with CLAG3.1 but make minimal contacts with each other. The forces stabilizing individual subunits include 13 intramolecular disulfide bonds. Notably, CLAG3.1 residues 1210 to 1223, previously predicted to constitute a transmembrane helix, are embedded within a helical bundle formed by residues 979 to 1289 near the C terminus of CLAG3.1. Buried in the core of the RhopH complex and largely shielded from solvent, insertion of this putative transmembrane helix into the erythrocyte membrane would likely require a large conformational rearrangement. Given the unusually high disulfide content of the complex, it is possible that such a rearrangement could be initiated by the breakage of allosteric disulfide bonds, potentially triggered by interactions at the erythrocyte membrane. This first direct observation of an exported
Identifiants
pubmed: 34446549
pii: 2100514118
doi: 10.1073/pnas.2100514118
pmc: PMC8536402
pii:
doi:
Substances chimiques
Protozoan Proteins
0
rhoptry-associated antigen-2, Plasmodium
145184-78-7
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NHLBI NIH HHS
ID : R00 HL133453
Pays : United States
Organisme : NIAID NIH HHS
ID : T32 AI007323
Pays : United States
Organisme : NIH HHS
ID : DP5 OD029613
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI094386
Pays : United States
Organisme : NIH HHS
ID : S10 OD018111
Pays : United States
Organisme : NHLBI NIH HHS
ID : K99 HL133453
Pays : United States
Organisme : NIDCR NIH HHS
ID : R01 DE025567
Pays : United States
Organisme : NCRR NIH HHS
ID : S10 RR023057
Pays : United States
Organisme : NIDCR NIH HHS
ID : R01 DE028583
Pays : United States
Organisme : NIGMS NIH HHS
ID : U24 GM116792
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM071940
Pays : United States
Informations de copyright
Copyright © 2021 the Author(s). Published by PNAS.
Déclaration de conflit d'intérêts
The authors declare no competing interest.
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