PMID- 28794035
OWN - NLM
STAT- MEDLINE
DCOM- 20171214
LR  - 20181113
IS  - 1098-5514 (Electronic)
IS  - 0022-538X (Print)
IS  - 0022-538X (Linking)
VI  - 91
IP  - 21
DP  - 2017 Nov 1
TI  - Crystal Structure of the DNA-Binding Domain of Human Herpesvirus 6A Immediate 
      Early Protein 2.
LID - 10.1128/JVI.01121-17 [doi]
LID - e01121-17
AB  - Immediate early proteins of human herpesvirus 6A (HHV-6A) are expressed at the 
      outset of lytic infection and thereby regulate viral gene expression. Immediate 
      early protein 2 (IE2) of HHV-6A is a transactivator that drives a variety of 
      promoters. The C-terminal region of HHV-6A IE2 is shared among IE2 homologs in 
      betaherpesviruses and is involved in dimerization, DNA binding, and transcription 
      factor binding. In this study, the structure of the IE2 C-terminal domain 
      (IE2-CTD) was determined by X-ray crystallography at a resolution of 2.5 A. 
      IE2-CTD forms a homodimer stabilized by a beta-barrel core with two interchanging 
      long loops. Unexpectedly, the core structure resembles those of the 
      gammaherpesvirus factors EBNA1 of Epstein-Barr virus and LANA of Kaposi 
      sarcoma-associated herpesvirus, but the interchanging loops are longer in IE2-CTD 
      and form helix-turn-helix (HTH)-like motifs at their tips. The HTH and 
      surrounding alpha-helices form a structural feature specific to the IE2 group. The 
      apparent DNA-binding site (based on structural similarity with EBNA1 and LANA) 
      resides on the opposite side of the HTH-like motifs, surrounded by positive 
      electrostatic potential. Mapping analysis of conserved residues on the 
      three-dimensional structure delineated a potential factor-binding site adjacent 
      to the expected DNA-binding site. The predicted bi- or tripartite functional 
      sites indicate a role for IE2-CTD as an adapter connecting the promoter and 
      transcriptional factors that drive gene expression.IMPORTANCE Human herpesvirus 
      6A (HHV-6A) and HHV-6B belong to betaherpesvirus subfamily. Both viruses 
      establish lifelong latency after primary infection, and their reactivation poses 
      a significant risk to immunocompromised patients. Immediate early protein 2 (IE2) 
      of HHV-6A and HHV-6B is a transactivator that triggers viral replication and 
      contains a DNA-binding domain shared with other betaherpesviruses such as human 
      herpesvirus 7 and human cytomegalovirus. In this study, an atomic structure of 
      the DNA-binding domain of HHV-6A IE2 was determined and analyzed, enabling a 
      structure-based understanding of the functions of IE2, specifically DNA 
      recognition and interaction with transcription factors. Unexpectedly, the dimeric 
      core resembles the DNA-binding domain of transcription regulators from 
      gammaherpesviruses, showing structural conservation as a DNA-binding domain but 
      with its own unique structural features. These findings facilitate further 
      characterization of this key viral transactivator.
CI  - Copyright (c) 2017 American Society for Microbiology.
FAU - Nishimura, Mitsuhiro
AU  - Nishimura M
AD  - Division of Clinical Virology, Kobe University Graduate School of Medicine, Kobe, 
      Japan.
FAU - Wang, Junjie
AU  - Wang J
AD  - Division of Clinical Virology, Kobe University Graduate School of Medicine, Kobe, 
      Japan.
FAU - Wakata, Aika
AU  - Wakata A
AD  - Division of Clinical Virology, Kobe University Graduate School of Medicine, Kobe, 
      Japan.
FAU - Sakamoto, Kento
AU  - Sakamoto K
AD  - Division of Clinical Virology, Kobe University Graduate School of Medicine, Kobe, 
      Japan.
FAU - Mori, Yasuko
AU  - Mori Y
AD  - Division of Clinical Virology, Kobe University Graduate School of Medicine, Kobe, 
      Japan ymori@med.kobe-u.ac.jp.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20171013
PL  - United States
TA  - J Virol
JT  - Journal of virology
JID - 0113724
RN  - 0 (IE2 protein, human herpesvirus 6A)
RN  - 0 (Immediate-Early Proteins)
RN  - 0 (Transcription Factors)
RN  - 0 (Viral Proteins)
RN  - 9007-49-2 (DNA)
SB  - IM
MH  - Amino Acid Sequence
MH  - Binding Sites
MH  - Crystallography, X-Ray
MH  - DNA/*metabolism
MH  - Humans
MH  - Immediate-Early Proteins/*chemistry/genetics/*metabolism
MH  - Protein Conformation
MH  - Sequence Homology
MH  - Transcription Factors/*metabolism
MH  - Transcriptional Activation
MH  - Viral Proteins/*chemistry/genetics/*metabolism
PMC - PMC5640841
OTO - NOTNLM
OT  - HHV-6
OT  - IE2
OT  - structure
EDAT- 2017/08/11 06:00
MHDA- 2017/12/15 06:00
PMCR- 2018/04/13
CRDT- 2017/08/11 06:00
PHST- 2017/07/03 00:00 [received]
PHST- 2017/07/03 00:00 [accepted]
PHST- 2017/08/11 06:00 [pubmed]
PHST- 2017/12/15 06:00 [medline]
PHST- 2017/08/11 06:00 [entrez]
PHST- 2018/04/13 00:00 [pmc-release]
AID - JVI.01121-17 [pii]
AID - 01121-17 [pii]
AID - 10.1128/JVI.01121-17 [doi]
PST - epublish
SO  - J Virol. 2017 Oct 13;91(21):e01121-17. doi: 10.1128/JVI.01121-17. Print 2017 Nov 
      1.