HHV capsid portal protein

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HHV Capsid Portal Protein, or HSV-1 UL-6 protein, is the protein which forms a cylindrical portal in the capsid of Herpes simplex virus (HSV-1). The protein is commonly referred to as the HSV-1 UL-6 protein because it is is the transcription product of Herpes gene UL-6.

The Herpes viral DNA enters and exits the capsid via the capsid portal. The capsid portal is formed by twelve copies of portal protein arranged as a ring; the proteins contain a leucine zipper sequence of amino acids which allow them to adhere to each other.[1] Each icosahedral capsid contains a single portal, located in one vertex. [2][3]

The portal is formed during initial capsid assembly and interacts with scaffolding proteins that construct the procapsid.[4] [5] [6] When the capsid is nearly complete, the viral DNA enters the capsid (i.e, the DNA is encapsidated) by a mechanism invovling the portal and a DNA-binding protein complex similar to bacteriophage terminase. [7] Multiple studies suggest an evolutionary relationship between Capsid Portal Protein and bacteriophage portal proteins.[2][7]

When virus infects a cell, it is necessary for the viral DNA to be released from the capsid. The Herpes virus DNA exits through the capsid portal.[8]

The genetic sequence of HSV-1 gene UL-6 is conserved across the Herpesviridae family and this family of genes is known as the "Herpesvirus UL6-like" gene family.[9] "UL-6" is nomenclature meaning that the protein is genetically encoded by the sixth (6th) open reading frame found in the viral genome segment named "Unique-Long (UL)".

Studies

Studies by amino acid sequence location
pUL-6 Amino acid range Summary Reference
E121, A618, Q621 Point mutations confer resistance to portal assembly inhibitor WAY-150138 van Zeijl, et al., 2000[10]
198-295 Deletion mutant forms immature B-capsids with no portals Nellissery, et al., 2007[3]
322-416 Deletion mutants form immature B-capsids which do contain portals Nellissery, et al., 2007[3]
409-473
L429, L436 Mutation studies suggest putative leucine zipper required for portal ring formation Nellissery, et al., 2007[3]
R676 Carboxyl (C)-terminal end NCBI Sequence[11]
pUL-26.5 "Scaffolding protein" Amino acid range Summary Reference
143-151 Deletion inhibits UL-6 portal assembly Singer, et al., 2005[6]


Dodecameric structure

Research performed in 2004 used electron microscopy to predict that UL-6 forms 11, 12, 13, and 14-unit polymers. The dodecameric (twelve-unit) form was found to be most likely.[2]

Refinements to the electron microscopy in 2007 allowed finding that the portal is a twelve (12)-unit polymer present at one of the twelve capsid vertices instead of the UL-19 pentamer found at non-portal vertices.[1]

Leucine zipper creates inter-protein adhesion

A study using deletion and mutation of the UL-6 amino acid sequence demonstrated the leucine residues in a predicuted leucine zipper motif were required for formation of the dodecameric ring sturcutre.[3]


Early involvement in capsid assembly

Assembly of portal units is an initial step in constructing capsids of viral progeny. Capsids assembled in the absence of portals lack portals.[4]

Interaction with capsid scaffolding protein

In 2003, gel eletrophoresis studies demonstrated that intact UL-6 portals associate in vitro with viral protein UL-26. This association is antagonized by that action of WAY-150138, a thiourea inhibitor of HHV encapsidation.[5]

Further investigation during 2006 showed that assembly of capsid with portal depends on interaction of UL-6 with "scaffolding" protein UL-26.5, amino acids 143 through 151. [6]

Interaction with terminase complex

UL-6 associates with a UL-15/UL-28 protein complex during capsid assembly. The UL-15/UL-28 is believed to bind with viral DNA and serve the same purpose as terminase by packing viral DNA into the capsid during capsid assembly. [7]

Function during DNA egress

The DNA exits the capsid in a single linear segment. DNA exit may be controlled by UL-6 and dependent on temperature or environmental proteins. [8]

Notes

  1. 1.0 1.1 Cardone G, Winkler DC, Trus BL, Cheng N, Heuser JE, Newcomb WW, Brown JC, Steven AC (2007 May 10). "Visualization of the herpes simplex virus portal in situ by cryo-electron tomography". Virology. 361 (2): 426-34. PMID 17188319. Check date values in: |date= (help)
  2. 2.0 2.1 2.2 Trus BL, Cheng N, Newcomb WW, Homa FL, Brown JC, Steven AC (2004 Nov). "Structure and polymorphism of the UL6 portal protein of herpes simplex virus type 1". Journal of Virology. 78 (22): 12668-71. PMID 15507654. Check date values in: |date= (help)(Article: [1])
  3. 3.0 3.1 3.2 3.3 3.4 Nellissery JK, Szczepaniak R, Lamberti C, Weller SK (2007 Jun 20). "A putative leucine zipper within the HSV-1 UL6 protein is required for portal ring formation". Journal Virology. PMID 17581990. Check date values in: |date= (help)
  4. 4.0 4.1 Newcomb WW, Homa FL, Brown JC (2005 Aug). "Involvement of the portal at an early step in herpes simplex virus capsid assembly". Journal of Virology. 79 (16): 10540-6. PMID 16051846. Check date values in: |date= (help)
  5. 5.0 5.1 Newcomb WW, Thomsen DR, Homa FL, Brown JC (2003 Sep). "Assembly of the herpes simplex virus capsid: identification of soluble scaffold-portal complexes and their role in formation of portal-containing capsids". Journal of Virology. 77 (18): 9862–71. PMID 12941896. Check date values in: |date= (help) (Article: [2])
  6. 6.0 6.1 6.2 Singer GP, Newcomb WW, Thomsen DR, Homa FL, Brown JC (2007 May 10. Epub 2006 Dec 22). "Identification of a region in the herpes simplex virus scaffolding protein required for interaction with the portal". Journal of Virology. 361 (2): 426-34. PMID 15596809. Check date values in: |date= (help) (Article: [3])
  7. 7.0 7.1 7.2 White CA, Stow ND, Patel AH, Hughes M, Preston VG (2003 Jun). "Herpes Simplex Virus Type 1 Portal Protein UL6 Interacts with the Putative Terminase Subunits UL15 and UL28". Journal of Virology. 77 (11): 6351-8. PMID 12743292. Check date values in: |date= (help)
  8. 8.0 8.1 Newcomb WW, Booy FP, Brown JC (2007 May 13). "Uncoating the Herpes Simplex Virus Genome". Journal of molecular biology. PMID 17540405. Check date values in: |date= (help)
  9. Herpesvirus UL6 like Conserved Domains view at NCBI
  10. Marja van Zeijl, Jeanette Fairhurst, Thomas R. Jones, Steven K. Vernon, John Morin, James LaRocque, Boris Feld, Bryan O'Hara, Jonathan D. Bloom, Stephen V. Johann (October 2000). "Novel Class of Thiourea Compounds That Inhibit Herpes Simplex Virus Type 1 DNA Cleavage and Encapsidation: Resistance Maps to the UL6 Gene". Journal of Virology. 74 (19): 9054-9061.
  11. HSV-1 UL-6 amino acid sequence at NCBI



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