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tisdag 21 oktober 2014

Miten EBOV trimmaa GP1:n musiinidomaanien kantajan


How Does Glycosylation of Ebola Virus Envelope Proteins Facilitate Immune Evasion?

In EBOV, four variants of the envelope glycoprotein are synthesized as a result of transcriptional stuttering or post-translational processing (Figure 1A). About 25% of transcripts from the GP gene produce the virion-attached or envelope spike GP that is important for entry. The surface of the envelope GP is covered with N- and O-linked glycans. Depending on the EBOV species, the envelope GP contains 11–18 N-linked glycan sites. Furthermore, EBOV GP contains an unstructured ~150-residue mucin-like domain that is heavily modified with O-linked glycans (~80 sites) [4]. The N-linked glycans are a heterogeneous mixture of ~60 different species of high-mannose, hybrid, and complex oligosaccharides, while the O-linked glycans consist of primarily smaller trisaccharide structures (core 2) that contain varying amounts of sialic acids [5].

Figure 1. Ebola virus glycoproteins.
(A) Processing of EBOV glycoproteins. The EBOV genome contains seven genes (3′-NP-VP35-VP40-GP-VP30-VP24-L-5′), but nine proteins are produced due to editing events in the GP gene.

The GP gene primary transcript encodes for a ~110 kDa, dimeric secreted GP (pre-sGP). Furin cleavage of pre-sGP produces mature sGP and a secreted Δ-peptide.

Transcriptional stuttering results in the production of the envelope-attached GP and a small, secreted GP (ssGP).

 The GP is the only virally encoded protein on the EBOV surface and is cleaved by furin to form a disulfide-linked GP1-GP2 heterodimer, which then assembles as trimers on the virus surface.

 GP1 contains the receptor-binding site for host cell attachment, while GP2 contains a helical heptad-repeat (HR) region, transmembrane anchor (TM), and a 4-residue cytoplasmic tail.

A cleavage at the membrane-proximal external region by the tumor necrosis factor-α converting enzyme (TACE) releases the shed GP.

The first 295 residues of ssGP, sGP, and GP are common, but each protein has a different C-terminus, leading to different functions.

 (B) Epitope masking by EBOV glycoproteins. Molecular surface of EBOV GP subunits (PDB code: 3CSY) are shown in green (GP1) and yellow (GP2).
Complex-type N-linked glycans are modeled onto the EBOV GP surface as red/white spheres to reveal a heavy glycan layer that buries much of the GP surface, including the receptor-binding site; only a small patch at the base of the GP is accessible (KZ52/16F6 antibody-binding site).
 The O-linked glycosylated mucin-like domain (blue) is modeled onto EBOV GP, and thought to form an extended structure that provides another glycan layer of protection to the virus.

 EBOV GP is estimated to be ~150 Å in height.
Given the size and shape of EBOV GP,
 smaller cellular surface proteins, such as MHC class I and β-integrins (~70 Å in height), may be sterically blocked.

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