Cervical cancer associated with infection by human papillomavirus (HPV) is the second leading cause of cancer deaths among women worldwide, resulting in one in six deaths. Understanding the assembly of HPV and the immune response to it offers multiple opportunities for pharmacologic and immunologic intervention to prevent disease or alter its course. Effective design of these interventions would be aided by knowledge of the structural basis of these phenomena.. Investigations to elucidate the structure of the HPV capsid and its antigenic epitopes are proposed. Because HPV does not readily replicate in cultured cells, it has been extremely difficult to study by the traditional techniques of virology and virus crystallography. To circumvent these limitations, a strategy that combines EM image reconstruction of HPV particles and HPV: antibody complexes with crystal structures of individual protein components is currently being executed. Information from image reconstruction will be combined with structures from crystallography by pseudo-atomic modeling. as applied to other system by the PPG group. With co PI Baker, we have completed a high resolution EM image reconstruction of HPV6b, and determined that it is quite reliable to at least 16 angstroms. Extension to higher accuracy and resolution and similar studies on HPV: antibody complexes will provide the data required for part of our strategy. For the other part, we have expressed both major and minor capsid proteins of HPV6b in a soluble form suitable for crystallization trials. While assembly of HPV is completely """"""""self-directed""""""""; assembly of many other biological structures occurs only with the aid of chaperone molecules. One system that employs chaperones is the assembly of the side tail fibers of phage lambda. Side tail fibers are very long, thin, jointed fibers found on wild-type lambda. These long fibers, trimmers of the Stf gene product, are analogous to similar fibers in other phages, and are formed only with the aim of the pTfa chaperone. The fibers increase efficiency of phage absorption to cells, presumably engaging a second receptor. Some studies suggest that, unlike any other chaperone, pTfa can act """"""""instructively"""""""" to alter the structure of the assembled fiber. To investigate this unusual behavior, pTfa has been the object of several attempts to crystallize the intact molecule. While all of these have failed to yield crystals suitable for x-ray diffraction, we have very recently grown crystals of a tryptic fragment of pTfa that diffract to beyond 2A. Determination of this structure and the structure of complexes of pTfa with suitable fragments of the very long, flexible Stf protein is proposed.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI045976-04
Application #
6652707
Study Section
Microbiology and Infectious Diseases Research Committee (MID)
Project Start
2002-09-01
Project End
2003-07-31
Budget Start
Budget End
Support Year
4
Fiscal Year
2002
Total Cost
Indirect Cost
Name
Purdue University
Department
Type
DUNS #
072051394
City
West Lafayette
State
IN
Country
United States
Zip Code
47907
Parent, Kristin N; Gilcrease, Eddie B; Casjens, Sherwood R et al. (2012) Structural evolution of the P22-like phages: comparison of Sf6 and P22 procapsid and virion architectures. Virology 427:177-88
Brodin, Jeffrey D; Ambroggio, X I; Tang, Chunyan et al. (2012) Metal-directed, chemically tunable assembly of one-, two- and three-dimensional crystalline protein arrays. Nat Chem 4:375-82
Kwon, Soonshin; Chen, Zack C Y; Kim, Ji-Hun et al. (2012) Misfit-guided self-organization of anticorrelated Ge quantum dot arrays on Si nanowires. Nano Lett 12:4757-62
Khadka, Sudip; Vangeloff, Abbey D; Zhang, Chaoying et al. (2011) A physical interaction network of dengue virus and human proteins. Mol Cell Proteomics 10:M111.012187
Tang, Jinghua; Lander, Gabriel C; Olia, Adam S et al. (2011) Peering down the barrel of a bacteriophage portal: the genome packaging and release valve in p22. Structure 19:496-502
Tang, Jinghua; Jose, Joyce; Chipman, Paul et al. (2011) Molecular links between the E2 envelope glycoprotein and nucleocapsid core in Sindbis virus. J Mol Biol 414:442-59
Ku, Ti-Hsuan; Chien, Miao-Ping; Thompson, Matthew P et al. (2011) Controlling and switching the morphology of micellar nanoparticles with enzymes. J Am Chem Soc 133:8392-5
Rossmann, Michael G; Battisti, Anthony J; Plevka, Pavel (2011) Future prospects. Adv Protein Chem Struct Biol 82:101-21
Shen, Peter S; Enderlein, Dirk; Nelson, Christian D S et al. (2011) The structure of avian polyomavirus reveals variably sized capsids, non-conserved inter-capsomere interactions, and a possible location of the minor capsid protein VP4. Virology 411:142-52
Yan, Xiaodong; Parent, Kristin N; Goodman, Russell P et al. (2011) Virion structure of baboon reovirus, a fusogenic orthoreovirus that lacks an adhesion fiber. J Virol 85:7483-95

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