Christopher W. Akey, Ph.D.

Phone:(617) 638-4051 • Fax: (617) 638-4041
e-mail: cakey@bu.edu
address: click here

Research

We are studying the structure and function of macromolecular machines and chaperones. In our work, we use biochemistry and molecular biology coupled with structural electron microscopy, X-ray crystallography and molecular modeling. This hybrid approach allows us to create snapshots of these large assemblies and thus, to infer function from form.

The apoptosome and other signaling platforms

In the intrinsic death pathway, cytochrome c binds to Apaf-1 and triggers apoptosome assembly in the presence of dATP. This platform binds procaspase-9, which activates procaspase-3 and other downstream procaspases. To understand this process, we determined a structure of the human apoptosome at 12.8Å resolution and created a model of this heptameric platform, which contains 49 domains and 7 cytochrome c molecules. Higher resolution studies of the active apoptosome should provide additional insights into the assembly and function of this cell killer. In parallel studies, we are determining structures of the Drosophila Apaf-1 related killer (Dark) and of other signaling platforms that mediate inflammatory responses to bacteria.

Ribosome-channel complexes

Nascent secretory proteins are translocated into the lumen of the ER. Conversely, membrane proteins are gated laterally into the lipid bilayer from the channel. We seek to create a model of the co-translational translocon to understand these processes. Thus, we have determined the structure of native ribosome-channel complexes. We have further refined the structure of the canine ribosome to ~8.0Å resolution and created a complete homology model of the mammalian ribosome. Current studies are now targeting translocation factors such as the translocon associated protein complex (TRAP) and the oligosacharryl transferase (OST). Finally, we are also studying the bacterial ribosome-channel complex to provide additional insights into translocation.

Histone chaperones

Histones must be chaperoned when they are not associated with DNA. However, little is known about this process. Nucleoplasmin-like chaperones form pentamers which may associate to form decamers when they bind histone tetramers or octamers. Current studies are aimed at obtaining structures of chaperones with their cognate histones to decipher the mechanism of binding.

The Type IVb secretion system of Legionella pneumophila

The T4bSS forms a channel that translocates bacterial proteins into the host eukaryotic cell. This process is required for infectivity by Legionella, a facultative pathogen. When alveolar macrophages are infected, this leads to a severe pneumonia (Legionnaires’ disease), which is particularly deadly in hospitals. We are studying the T4bSS with the goal of creating a molecular model of its function. As a first step, we determined the crystal structure of the interacting domains of IcmR-IcmQ (Rm-Qn). IcmR is a chaperone that prevents IcmQ from inserting into membranes. IcmQ may then form extensive links between membranes to help assemble or stabilize the T4bSS. We are now focusing on other components of this protein translocase.

Selected Publications:

Yu, X., Wang, L., Acehan, D., Wang, X. and Akey, C.W. (2006). Three-dimensional structure of a double apoptosome formed by the Drosophila Apaf-1 related killer. J. Mol. Biol. 355, 577-589.

Yu, X., Acehan, D., Ménétret, J.F., Booth, C.R., Ludtke, S.J., Riedl, S. J., Shi, Y., Wang, X. and Akey, C.W. (2005). A structure of the human apoptosome at 12.8Å resolution provides insights into this cell death platform. Structure 13, 1725-1735.

Ménétret, J. F., Hegde, R.S., Heinrich S., Chandramouli, P., Ludtke, S.J., Rapoport, T. A., and Akey, C. W. (2005). Architecture of the ribosome-channel complex derived from native membranes. J. Mol. Biol. 348, 445-457.

Clemons Jr., W.M., Ménétret, J. F., Akey, C.W. and Rapoport, T. A. (2004). Structural insight into the protein translocation channel. Curr. Op. Struct. Biol. 14, 390-396.

Namboodiri, H.V.M., Akey, I.V., Schmidt-Zachmann, M.S., Head, J.F. and Akey, C.W. (2004). Structure and function of Xenopus NO38-core, a histone chaperone in the nucleolus. Structure 12, 2149-2160.

Namboodiri, H.V.M., Dutta, S., Akey, I.V., Head, J.F. and Akey, C.W. (2003). The crystal structure of Drosophila NLP-core at 1.5Å resolution provides insight into pentamer formation and histone binding. Structure 11, 175-186.

Akey, C.W. and  Luger, K. (2003). Histone chaperones and nucleosome assembly. Curr. Op. Struct. Biol. 13, 6-14.

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Contact Us

Department of Physiology and Biophysics
Boston University School of Medicine
700 Albany Street
Boston MA 02118-2526

Phone:(617) 638-4051
Fax: (617) 638-4041
e-mail: cakey@bu.edu