PMID- 26712012
OWN - NLM
STAT- MEDLINE
DCOM- 20160614
LR  - 20181113
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 113
IP  - 2
DP  - 2016 Jan 12
TI  - Dissecting the interface between apicomplexan parasite and host cell: Insights 
      from a divergent AMA-RON2 pair.
PG  - 398-403
LID - 10.1073/pnas.1515898113 [doi]
AB  - Plasmodium falciparum and Toxoplasma gondii are widely studied parasites in 
      phylum Apicomplexa and the etiological agents of severe human malaria and 
      toxoplasmosis, respectively. These intracellular pathogens have evolved a 
      sophisticated invasion strategy that relies on delivery of proteins into the host 
      cell, where parasite-derived rhoptry neck protein 2 (RON2) family members 
      localize to the host outer membrane and serve as ligands for apical membrane 
      antigen (AMA) family surface proteins displayed on the parasite. Recently, we 
      showed that T. gondii harbors a novel AMA designated as TgAMA4 that shows extreme 
      sequence divergence from all characterized AMA family members. Here we show that 
      sporozoite-expressed TgAMA4 clusters in a distinct phylogenetic clade with 
      Plasmodium merozoite apical erythrocyte-binding ligand (MAEBL) proteins and forms 
      a high-affinity, functional complex with its coevolved partner, TgRON2L1. 
      High-resolution crystal structures of TgAMA4 in the apo and TgRON2L1-bound forms 
      complemented with alanine scanning mutagenesis data reveal an unexpected 
      architecture and assembly mechanism relative to previously characterized AMA-RON2 
      complexes. Principally, TgAMA4 lacks both a deep surface groove and a key surface 
      loop that have been established to govern RON2 ligand binding selectivity in 
      other AMAs. Our study reveals a previously underappreciated level of molecular 
      diversity at the parasite-host-cell interface and offers intriguing insight into 
      the adaptation strategies underlying sporozoite invasion. Moreover, our data 
      offer the potential for improved design of neutralizing therapeutics targeting a 
      broad range of AMA-RON2 pairs and apicomplexan invasive stages.
FAU - Parker, Michelle L
AU  - Parker ML
AD  - Department of Biochemistry and Microbiology, University of Victoria, Victoria, 
      BC, V8P 5C2, Canada;
FAU - Penarete-Vargas, Diana M
AU  - Penarete-Vargas DM
AD  - UMR 5235, CNRS Universite Montpellier, 34095 Montpellier, France;
FAU - Hamilton, Phineas T
AU  - Hamilton PT
AD  - Department of Biology, University of Victoria, Victoria, BC, V8P 5C2, Canada;
FAU - Guerin, Amandine
AU  - Guerin A
AD  - UMR 5235, CNRS Universite Montpellier, 34095 Montpellier, France;
FAU - Dubey, Jitender P
AU  - Dubey JP
AD  - Animal Parasitic Diseases Laboratory, Beltsville Agricultural Research Center, 
      Agricultural Research Service, United States Department of Agriculture, 
      Beltsville, MD 20705-2350;
FAU - Perlman, Steve J
AU  - Perlman SJ
AD  - Department of Biology, University of Victoria, Victoria, BC, V8P 5C2, Canada;
FAU - Spano, Furio
AU  - Spano F
AD  - Department of Infectious, Parasitic and Immunomediated Diseases, Istituto 
      Superiore di Sanita, Rome 00161, Italy.
FAU - Lebrun, Maryse
AU  - Lebrun M
AD  - UMR 5235, CNRS Universite Montpellier, 34095 Montpellier, France; 
      mboulang@uvic.ca mylebrun@univ-montp2.fr.
FAU - Boulanger, Martin J
AU  - Boulanger MJ
AD  - Department of Biochemistry and Microbiology, University of Victoria, Victoria, 
      BC, V8P 5C2, Canada; mboulang@uvic.ca mylebrun@univ-montp2.fr.
LA  - eng
SI  - PDB/4Z80
SI  - PDB/4Z81
GR  - MOP82915/Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20151228
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Protozoan Proteins)
RN  - 0 (rhoptry neck protein 2, Toxoplasma gondii)
SB  - IM
MH  - Animals
MH  - *Host-Parasite Interactions
MH  - Mice
MH  - Models, Molecular
MH  - Parasites/*physiology
MH  - Phylogeny
MH  - Protein Binding
MH  - Protozoan Proteins/chemistry/*metabolism
MH  - Toxoplasma/*metabolism
PMC - PMC4720339
OTO - NOTNLM
OT  - Apicomplexa
OT  - Toxoplasma gondii
OT  - X-ray crystallography
OT  - invasion
OT  - moving junction
COIS- The authors declare no conflict of interest.
EDAT- 2015/12/30 06:00
MHDA- 2016/06/15 06:00
PMCR- 2016/07/12
CRDT- 2015/12/30 06:00
PHST- 2015/12/30 06:00 [entrez]
PHST- 2015/12/30 06:00 [pubmed]
PHST- 2016/06/15 06:00 [medline]
PHST- 2016/07/12 00:00 [pmc-release]
AID - 1515898113 [pii]
AID - 201515898 [pii]
AID - 10.1073/pnas.1515898113 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2016 Jan 12;113(2):398-403. doi: 
      10.1073/pnas.1515898113. Epub 2015 Dec 28.