GP1 of Lassa Virus: Difference between revisions

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'''GP1''' (Glycoprotein 1) is the receptor binding domain of LASV that mediates receptor recognition. Research thus far indicates that GP1 from LASV may undergo irreversible conformational changes that could serve as an immunological decoy mechanism. Arenaviruses utilize various cell surface proteins as their cellular receptors for recognizing and attaching to target cells. New World (NW) arenaviruses that belong to clades A and B use transferrin receptor 1 (TfR1)<ref name="PMID:17287727">PMID:17287727</ref><ref name="PMID:24920811">PMID:24920811</ref>, whereas OW arenaviruses, as well as clade C NW arenaviruses, use α-dystroglycan (α-DG) <ref name="PMID:9851928">PMID:9851928</ref><ref name="PMID:15857984">PMID:15857984</ref><ref name="PMID:11967329">PMID:11967329</ref>. A trimeric class 1 viral glycoprotein complex (the spike complex) recognizes the cellular receptors and mediates membrane fusion upon exposure to low pH at the lysosome <ref name="PMID:16731928">PMID:16731928</ref>. The spike complex is expressed as a glycoprotein precursor that is cleaved into three segments by a signal peptidase and SKI-1/S1P protease<ref name="PMID:21612810">PMID:21612810</ref>. The functional spike complex consists of GP1, a membrane-anchored fusion protein (GP2), and a unique structured SSP <ref name="PMID:23202458">PMID:23202458</ref>.                                                                                                                                                                                                                                                                                                                                                                                         
'''GP1''' (Glycoprotein 1) is the receptor binding domain of LASV that mediates receptor recognition. Research thus far indicates that GP1 from LASV may undergo irreversible conformational changes that could serve as an immunological decoy mechanism. Arenaviruses utilize various cell surface proteins as their cellular receptors for recognizing and attaching to target cells. New World (NW) arenaviruses that belong to clades A and B use transferrin receptor 1 (TfR1)<ref name="PMID:17287727">PMID:17287727</ref><ref name="PMID:24920811">PMID:24920811</ref>, whereas OW arenaviruses, as well as clade C NW arenaviruses, use α-dystroglycan (α-DG) <ref name="PMID:9851928">PMID:9851928</ref><ref name="PMID:15857984">PMID:15857984</ref><ref name="PMID:11967329">PMID:11967329</ref>. A trimeric class 1 viral glycoprotein complex (the spike complex) recognizes the cellular receptors and mediates membrane fusion upon exposure to low pH at the lysosome <ref name="PMID:16731928">PMID:16731928</ref>. The spike complex is expressed as a glycoprotein precursor that is cleaved into three segments by a signal peptidase and SKI-1/S1P protease<ref name="PMID:21612810">PMID:21612810</ref>. The functional spike complex consists of GP1, a membrane-anchored fusion protein (GP2), and a unique structured SSP <ref name="PMID:23202458">PMID:23202458</ref>.                                                                                                                                                                                                                                                                                                                                                                                         
==Structural Highlights==
==Structural Highlights==
GP1 of LASV is a single chain structure with attached <scene name='76/761695/Nag/4'>NAG</scene> glycans. The overall architecture of GP1 features a central β-sheet and two distinct halves: a glycosylated half containing the receptor-binding site that is made mostly by the central β-sheet and surrounding loops and a half that contains mostly helices and most likely faces the trimer axis<ref name="PMID: 25972533">PMID: 25972533</ref>, as determined in the Diskin laboratory at the Weizmann Institute of Science.. The method used to determine this structure was [http://en.wikipedia.org/wiki/X-ray_crystallography X-ray diffraction]
GP1 of LASV is a single chain structure with attached <scene name='76/761695/Nag/4'>NAG</scene> glycans. The overall architecture of GP1 features a central β-sheet and two distinct halves: a glycosylated half containing the receptor-binding site that is made mostly by the central β-sheet and surrounding loops and a half that contains mostly helices and most likely faces the trimer axis<ref name="PMID: 25972533">PMID: 25972533</ref>, as determined in the Diskin laboratory at the Weizmann Institute of Science. The method used to determine this structure was [http://en.wikipedia.org/wiki/X-ray_crystallography X-ray diffraction]
===LAMP1 Binding Site===
===LAMP1 Binding Site===
The primary cellular receptor of LASV is α-dystroglycan (α-DG)<ref name="PMID: 9851928">PMID: 9851928</ref><ref name="PMID: 15857984">PMID: 15857984</ref>, which is recognized by a trimeric class 1 viral GPC (spike complex) on the viral surface<ref name="PMID: 16731928">PMID: 16731928</ref><ref name="PMID: 26849049">PMID: 26849049</ref>. Following successful attachment to α-DG on cells, LASV is internalized via [http://en.wikipedia.org/wiki/Pinocytosis macropinocytosis]<ref name="PMID: 27147735">PMID: 27147735</ref>, and the GPC facilitates membrane fusion at the acidic environment of a late endosomal compartment<ref name="PMID: 16731928"><ref name="PMID: 21931550">PMID: 21931550 </ref>. Recent studies have shown that successful infection by LASV requires it to switch in a pH-dependent manner from α-DG to LAMP1<ref name="PMID: 27605678" /><ref name="PMID:24970085">PMID:24970085</ref>. Binding of the <scene name='76/761695/Lamp1bindingsite/14'>LAMP1</scene> endosomal compartment triggers the spikes.
The primary cellular receptor of LASV is α-dystroglycan (α-DG)<ref name="PMID: 9851928">PMID: 9851928</ref><ref name="PMID: 15857984">PMID: 15857984</ref>, which is recognized by a trimeric class 1 viral GPC (spike complex) on the viral surface<ref name="PMID: 16731928">PMID: 16731928</ref><ref name="PMID: 26849049">PMID: 26849049</ref>. Following successful attachment to α-DG on cells, LASV is internalized via [http://en.wikipedia.org/wiki/Pinocytosis macropinocytosis]<ref name="PMID: 27147735">PMID: 27147735</ref>, and the GPC facilitates membrane fusion at the acidic environment of a late endosomal compartment<ref name="PMID: 16731928"><ref name="PMID: 21931550">PMID: 21931550 </ref>. Recent studies have shown that successful infection by LASV requires it to switch in a pH-dependent manner from α-DG to LAMP1<ref name="PMID: 27605678" /><ref name="PMID:24970085">PMID:24970085</ref>. Binding of the <scene name='76/761695/Lamp1bindingsite/14'>LAMP1</scene> endosomal compartment triggers the spikes.
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