Page 47 - TBE_Book_V2_2019

Chapter 2b

The molecular and

antigenic structure of TBEV

Franz-Xaver Heinz and Karin Stiasny

Key Points

• TBEV-particles are assembled in an immature, noninfectious form in the endoplasmic reticulum by
the envelopment of the viral core (containing the viral RNA) by a lipid membrane associated with
two viral proteins, prM and E.
• Immature particles are transported through the cellular exocytic pathway and conformational
changes induced by acidic pH in the trans-Golgi network allow the proteolytic cleavage of prM by
furin, a cellular protease, resulting in the release of mature and infectious TBE-virions.

• The E protein controls cell entry by mediating attachment to as yet ill-defined receptors as well as
by low-pH-triggered fusion of the viral and endosomal membrane after uptake by receptor-
mediated endocytosis.
• Because of its key functions in cell entry, the E protein is the primary target of virus neutralizing
antibodies, which inhibit these functions by different mechanisms.

• Although all flavivirus E proteins have a similar overall structure, divergence at the amino acid
sequence level is up to 60 percent (e.g. between TBE and dengue viruses), and therefore cross-
neutralization as well as (some degree of) cross-protection are limited to relatively closely related
flaviviruses, such as those constituting the tick-borne encephalitis serocomplex.

Introduction

Tick-borne encephalitis virus (TBEV) has played 34,300 embryonated eggs were used for the
a pioneering role in the history of flavivirus preparation of primary chick embryo cells that
structural biology, being the first of these were required for growing the virus. First
viruses for which a high atomic resolution structural details became visible in 1993, and
structure of the envelope glycoprotein E was the complete study was finally published in
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determined (Figure 1A). This undertaking 1995.
started 1987 in a collaboration between
researchers at the Institute of Virology, The structure of sE was a great surprise because
University of Vienna, (now Center for Virology, of its unexpected features. In stark contrast to
Medical University of Vienna), and the Depart- the prototypic influenza envelope glycoprotein
ment of Biochemistry, Harvard University. The (hemagglutinin, HA), which forms spiky
work took several years and required the projections of HA trimers at the viral surface,
purification of a total of 49 mg of a soluble form the TBEV E protein is an antiparallel dimer that
of the TBEV E protein (sE) that was isolated by is oriented horizontally to the viral membrane
trypsin cleavage from 401 mg of purified (Figure 1 A,B). Each of the monomeric sE
infectious TBEV. To obtain these amounts, subunits contains three domains (DI, DII, and

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