Structural and functional comparison of the non-structural protein 4B in flaviviridae.
Flaviviridae are evolutionarily related viruses, comprising the hepatitis C virus (HCV), with the non-structural protein 4B (NS4B) as one of the least characterized proteins. NS4B is located in the endoplasmic reticulum membrane and is assumed to be a multifunctional protein. However, detailed structure information is missing. The hydrophobic nature of NS4B is a major difficulty for many experimental techniques. We applied bioinformatics methods to analyse structural and functional properties of NS4B in different viruses. We distinguish a central non-globular membrane portion with four to five transmembrane regions from an N- and C-terminal part with non-transmembrane helical elements. We demonstrate high similarity in sequence and structure for the C-terminal part within the flaviviridae family. A palmitoylation site contained in the C-terminal part of HCV is equally conserved in GB virus B. Furthermore, we identify and characterize an N-terminal basic leucine zipper (bZIP) motif in HCV, which is suggestive of a functionally important interaction site. In addition, we model the interaction of the bZIP region with the recently identified interaction partner CREB-RP/ATF6beta, a human activating transcription factor involved in ER-stress. In conclusion, the versatile structure, together with functional sites and motifs, possibly enables NS4B to adopt a role as protein hub in the membranous web interaction network of virus and host proteins. Important structural and functional properties of NS4B are predicted with implications for ER-stress response, altered gene expression and replication efficacy.
Welsch
Christoph
C
Internal Medicine II, Saarland University Hospital, Kirrberger Strasse, 66421 Homburg/Saar, Germany. christoph.welsch@uniklinikum-saarland.de
Albrecht
Mario
M
Maydt
Jochen
J
Herrmann
Eva
E
Welker
Martin Walter
MW
Sarrazin
Christoph
C
Scheidig
Axel
A
Lengauer
Thomas
T
Zeuzem
Stefan
S
D000595:Amino Acid Sequence; D003198:Computer Simulation; D004721:Endoplasmic Reticulum / Q000378:metabolism; D018067:Flaviviridae / Q000378:metabolism*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010802:Phylogeny; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D017361:Viral Nonstructural Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
C080107:NS4B protein, flavivirus; D017361:Viral Nonstructural Proteins