JVI Accepts, published online ahead of print on 18 June 2008

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J. Virol. doi:10.1128/JVI.00509-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Structural Analysis Reveals an Amyloid Form of the HPV 16 E1^E4 Protein and Provides a Molecular Basis for its Accumulation

Pauline B. McIntosh^*, Stephen R. Martin, Deborah J. Jackson, Jameela Khan, Erin R. Isaacson, Lesley Calder, Kenneth Raj, Heather M. Griffin, Qian Wang, Peter Laskey, John F. Eccleston, and John Doorbar

Division of Virology, Division of Physical Biochemistry, MRC National Institute for Medical Research, London NW7 1AA, UK

^* To whom correspondence should be addressed. Email: pmcinto{at}nimr.mrc.ac.uk.

The abundant HPV 16 E4 protein exists as two distinct structural forms in differentiating epithelial cells. Monomeric full-length 16E1E4 contains a limited tertiary fold constrained by the N and C-termini. N-terminal deletion facilitates assembly of E1E4 into amyloid-like fibrils, which bind to thioflavin T. The C-terminal region is highly amyloidogenic and its deletion abolishes amyloid staining and prevents E1E4 accumulation. Amyloid-imaging probes can detect 16E1E4 in biopsy material, as well as 18E1E4 and 33E1E4 in monolayer cells indicating structural conservation. Our results suggest a role for fibril formation in facilitating the accumulation of E4 during HPV infection.

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