Structural and Biochemical Characterization of the Conserved Herpesviral Protein UL37.
Koenigsberg, Andrea.
2019
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In all herpesviruses,
the space between the capsid shell and the lipid envelope is occupied by the unique
tegument layer composed of proteins that, in addition to maintaining the structure of
the viral replication, play many other roles in viral replication. UL37 is a highly
conserved tegument protein that has activities ranging from virion morphogenesis to
directional capsid trafficking and ... read moremanipulation of the host innate immune response and
binds multiple viral and host protein partners. However, the underlying mechanism of how
UL37 can accomplish all these functions remains unknown. In this work we, we took
structural and biochemical approaches to better understand the multifunctionality of
UL37. Here, we report the crystal structure of the N-terminal half of UL37 (UL37N) from
Herpes Simplex Virus type 1 (HSV-1). Comparison with the previously reported crystal
structure UL37N from the related pseudorabies virus (PRV) revealed that UL37 homologs
differ in their overall shapes, distributions of charges, and locations of projecting
loops. In contrast, the previously identified R2 surface region is structurally
conserved. The R2 region was identified using evolutionary trace analysis (ETA) and five
alanine mutations within the R2 region specifically abolish retrograde capsid
trafficking in neurons, blocking neuroinvasion in both PRV and HSV-1. We propose that
within the N-terminal half of UL37, functional conservation is centered within the R2
surface region, whereas divergent structural elements pinpoint regions mediating
virus-specific functions. The two structures of UL37N can now serve as templates for a
structure-guided exploration of both conserved and virus-specific functions.
Additionally, no previous biochemical or structural information was available for the
C-terminal half of UL37 (UL37C) that mediates most of its interactions with multiple
binding partners. Here, we show that UL37C from PRV is a conformationally flexible
monomer composed of an elongated folded core and an unstructured C-terminal tail. This
elongated structure, along with that of its binding partner UL36, explains the nature of
filamentous tegument structures bridging the capsid and the envelope. We propose that
the dynamic nature of UL37 underlies its ability to perform diverse roles during viral
replication.
Thesis (Ph.D.)--Tufts University, 2019.
Submitted to the Dept. of Molecular Microbiology.
Advisor: Ekaterina Heldwein.
Committee: Ralph Isberg, Marta Gaglia, Andrew Bohm, and Sun Hur.
Keyword: Biochemistry.read less - ID:
- fn107b83w
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