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Journal of Virology, July 2003, p. 7225-7235, Vol. 77, No. 13
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.13.7225-7235.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Flexibility of the Adenovirus Fiber Is Required for Efficient Receptor Interaction{dagger}

Eugene Wu,1 Lars Pache,1,{ddagger} Dan J. Von Seggern,1 Tina-Marie Mullen,1 Yeshi Mikyas,2 Phoebe L. Stewart,2,3 and Glen R. Nemerow1*

Department of Immunology, The Scripps Research Institute, La Jolla, California 92037,1 Department of Molecular and Medical Pharmacology, Crump Institute for Molecular Imaging, UCLA School of Medicine, Los Angeles, California 90095,2 Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-06153

Received 6 December 2002/ Accepted 15 April 2003

The adenovirus (Ad) fiber protein mediates Ad binding to the coxsackievirus and Ad receptor (CAR) and is thus a major determinant of viral tropism. The fiber contains three domains: an N-terminal tail that anchors the fiber to the viral capsid, a central shaft region of variable length and flexibility, and a C-terminal knob domain that binds to cell receptors. Ad type 37 (Ad37), a subgroup D virus associated with severe ocular infections, is unable to use CAR efficiently to infect host cells, despite containing a CAR binding site in its fiber knob. We hypothesized that the relatively short, inflexible Ad37 fiber protein restricts interactions with CAR at the cell surface. To test this hypothesis, we analyzed the infectivity and binding of recombinant Ad particles containing modified Ad37 or Ad5 fiber proteins. Ad5 particles equipped with a truncated Ad5 fiber or with a chimeric fiber protein comprised of the Ad5 knob fused to the short, rigid Ad37 shaft domain had significantly reduced infectivity and attachment. In contrast, placing the Ad37 knob onto the long, flexible Ad5 shaft allowed CAR-dependent virus infection and cell attachment, demonstrating the importance of the shaft domain in receptor usage. Increasing fiber rigidity by substituting the predicted flexibility modules in the Ad5 shaft with the corresponding regions of the rigid Ad37 fiber dramatically reduced both virus infection and cell attachment. Cryoelectron microscopy (cryo-EM) single-particle analysis demonstrated the increased rigidity of this chimeric fiber. These studies demonstrate that both length and flexibility of the fiber shaft regulate CAR interaction and provide a molecular explanation for the use of alternative receptors by subgroup D Ad with ocular tropism. We present a molecular model for Ad-CAR interactions at the cell surface that explains the significance of fiber flexibility in cell attachment.

* Corresponding author. Mailing address: Department of Immunology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 784-8072. Fax: (858) 784-8472. E-mail: gnemerow{at}scripps.edu.

{dagger} This is manuscript 15323-IMM from The Scripps Research Institute.

{ddagger} Present address: Eingereicht am Fachbereich Biologie, Chemie, Pharmazie, Institut für Chemie der Freien Universität Berlin, Berlin, Germany.

Journal of Virology, July 2003, p. 7225-7235, Vol. 77, No. 13
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.13.7225-7235.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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