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A near atomic structure of the active human apoptosome

Tat Cheung Cheng, Chuan Hong, Ildikó V Akey, Shujun Yuan, Christopher W Akey
2016 eLife  
Additional information Funding Funder Grant reference number Author National Institutes of Health GM063834 Christopher W Akey The funders had no role in study design, data collection and interpretation  ...  The sequential addition of further subunits would then overcome entropic barriers to favor apoptosome assembly reviewed in Yuan and Akey, 2013) .  ...  W Akey, Additional files Major datasets The following datasets were generated:  ... 
doi:10.7554/elife.17755 pmid:27697150 pmcid:PMC5050015 fatcat:27ldsuq6szggfgpol2k5qd2ohm

Apoptosome Structure, Assembly, and Procaspase Activation

Shujun Yuan, Christopher W. Akey
2013 Structure  
Apaf-1-like molecules assemble into a ring-like platform known as the apoptosome. This cell death platform then activates procaspases in the intrinsic cell death pathway. In this review, crystal structures of Apaf-1 monomers and CED-4 dimers have been combined with apoptosome structures to provide insights into the assembly of cell death platforms in humans, nematodes, and flies. In humans, the caspase recognition domains (CARDs) of procaspase-9 and Apaf-1 interact with each other to form a
more » ... -CARD disk, which interacts with the platform to create an asymmetric proteolysis machine. The disk tethers multiple pc-9 catalytic domains to the platform to raise their local concentration, and this leads to zymogen activation. These findings have now set the stage for further studies of this critical activation process on the apoptosome.
doi:10.1016/j.str.2013.02.024 pmid:23561633 pmcid:PMC3644875 fatcat:b324tjnunbenvogvsxd4b4x2re

Crystal Structure and Function of Human Nucleoplasmin (Npm2): A Histone Chaperone in Oocytes and Embryos

Olga Platonova, Ildikó V. Akey, James F. Head, Christopher W. Akey
2011 Biochemistry  
Human Npm2 is an ortholog of Xenopus nucleoplasmin (Np), a chaperone that binds histones. We have determined the crystal structure of a truncated Npm2-core at 1.9Å resolution and show that the N-terminal domains of Npm2 and Np form similar pentamers. This allowed us to model an Npm2 decamer which may be formed by hydrogen bonds between quasi-conserved residues in the interface between two pentamers. Interestingly, the Npm2 pentamer lacks a prototypical A1-acidic tract in each of its subunits.
more » ... is feature may be responsible for the inability of Npm2-core to bind histones. However, Npm2 with a large acidic tract in its C-terminal tail (Npm2-A2) is able to bind histones and form large complexes. Fluorescence resonance energy transfer experiments and biochemical analysis of loop mutations support the premise that nucleoplasmins form decamers when they bind H2A-H2B dimers and H3-H4 tetramers simultaneously. In the absence of histone tetramers, these chaperones bind H2A-H2B dimers with a single pentamer forming the central hub. When taken together, our data provide insights into the mechanism of histone binding by nucleoplasmins.
doi:10.1021/bi2006652 pmid:21863821 pmcid:PMC3172369 fatcat:t73qssjyvzbwlb6ilb42r2zu3u

The NPC-Transporter, A Ghost in the Machine

Christopher W. Akey
2010 Structure  
Reproduced from Akey and Radermacher (1993).  ...  ., 1998; Akey and Radermacher, 1993) , as well as in FEISEM images (Allen et al., 2000) .  ... 
doi:10.1016/j.str.2010.09.005 pmid:20947011 pmcid:PMC2966715 fatcat:vrgl6vzb7jb7ppgp5wbgy55zj4

The Crystal Structure of Drosophila NLP-Core Provides Insight into Pentamer Formation and Histone Binding

V.M.Haridasan Namboodiri, Shuchismita Dutta, Ildikó V Akey, James F Head, Christopher W Akey
2003 Structure  
., Akey, I.V., Dingwall, C., Hartman, K.L., Laue, T., Nolte, Thermal stability assays were carried out on the purified proteins R.T., Head, J.F., and Akey, C.W. (2001).  ... 
doi:10.1016/s0969-2126(03)00007-8 pmid:12575937 fatcat:4el7kmiswzdafbr2jzezeqzqae

Oxidized or Reduced Cytochrome c and Axial Ligand Variants All Form the Apoptosome in Vitro

Deanna L. Mendez, Ildikó V. Akey, Christopher W. Akey, Robert G. Kranz
2017 Biochemistry  
NIH GM063834 to Christopher W. Akey.  ... 
doi:10.1021/acs.biochem.7b00309 pmid:28510448 pmcid:PMC5551479 fatcat:lgmpzy6obreedadre2q2fztqsa

The Structure and Function of Xenopus NO38-Core, a Histone Chaperone in the Nucleolus

V.M.Haridasan Namboodiri, Ildikó V. Akey, Marion S. Schmidt-Zachmann, James F. Head, Christopher W. Akey
2004 Structure  
References Chaperone histone complexes were made with a rapid desalting method, by mixing the components at a final concentration of ‫01ف‬ Akey, C.W., and Luger, K. (2003).  ... 
doi:10.1016/j.str.2004.09.017 pmid:15576029 fatcat:w7zmgdqwsfcejc5jsz73qswoae

IcmQ in the Type 4b Secretion System Contains an NAD+ Binding Domain

Jeremiah D. Farelli, James C. Gumbart, Ildikó V. Akey, Andrew Hempstead, Whitney Amyot, James F. Head, C. James McKnight, Ralph R. Isberg, Christopher W. Akey
2013 Structure  
Trypsin (1,000:1 w/w; Sigma) was added to the complex for 2 hr, prior to protease removal by passage over agarose-linked benzamidine.  ... 
doi:10.1016/j.str.2013.05.017 pmid:23850453 pmcid:PMC3816012 fatcat:uzrv3ecjobaetjnh6qrftiiw6a

Three-Dimensional Structure of the Apoptosome

Devrim Acehan, Xuejun Jiang, David Gene Morgan, John E Heuser, Xiaodong Wang, Christopher W Akey
2002 Molecular Cell  
Correspondence:  ... 
doi:10.1016/s1097-2765(02)00442-2 pmid:11864614 fatcat:oqfh5t5kwfasfcq5qdcgqs5lry

Changes in Apaf-1 Conformation That Drive Apoptosome Assembly

Shujun Yuan, Maya Topf, Thomas F. Reubold, Susanne Eschenburg, Christopher W. Akey
2013 Biochemistry  
Apoptosome assembly is highly regulated in the intrinsic cell death pathway. To better understand this step, we created an improved model of the human apoptosome using a crystal structure of full length Apaf-1 and a single particle, electron density map at ~9.5Å resolution. The apoptosome model includes N-terminal domains of Apaf-1, cognate β-propellers and cytochrome c. A direct comparison of Apaf-1 in the apoptosome and as a monomer reveals conformational changes that occur during the first
more » ... o steps of assembly. This includes an induced-fit mechanism for cytochrome c binding to regulatory β-propellers, which is dependent on shape and charge complimentarity, and a large rotation of the nucleotide binding module during nucleotide exchange. These linked conformational changes create an extended Apaf-1 monomer and drive apoptosome assembly. Moreover, the N-terminal CARD in the inactive Apaf-1 monomer is not shielded from other proteins by β-propellers. Hence, the Apaf-1 CARD may be free to interact with a procaspase-9 CARD either before or during apoptosome assembly. Irrespective of the timing, the end product of assembly is a holo-apoptosome with an acentric CARD-CARD disk and tethered pc-9 catalytic domains. Subsequent activation of pc-9 leads to a proteolytic cascade and cell death.
doi:10.1021/bi301721g pmid:23521171 pmcid:PMC3645920 fatcat:ioiqgyerfveozogxo5wvblyfri

Structure of an Apoptosome-Procaspase-9 CARD Complex

Shujun Yuan, Xinchao Yu, Maya Topf, Steven J. Ludtke, Xiaodong Wang, Christopher W. Akey
2010 Structure  
Apaf-1 coassembles with cytochrome c to form the apoptosome, which then binds and activates procaspase-9 (pc-9). We removed pc-9 catalytic domains from the holoapoptosome by site-directed thrombinolysis. A structure of the resulting apoptosome-pc-9 CARD complex was then determined at 9.5 Å resolution. In our model, the central hub is constructed like other AAA+ protein rings but also contains novel features. At higher radius, the regulatory region of each Apaf-1 is comprised of tandem seven and
more » ... eight blade b-propellers with cytochrome c docked between them. Remarkably, Apaf-1 CARDs are disordered in the ground state. During activation, each Apaf-1 CARD interacts with a pc-9 CARD and these heterodimers form a flexibly tethered "disk" that sits above the central hub. When taken together, the data reveal conformational changes during Apaf-1 assembly that allow pc-9 activation. The model also provides a plausible explanation for the effects of NOD mutations that have been mapped onto the central hub.
doi:10.1016/j.str.2010.04.001 pmid:20462491 pmcid:PMC2874686 fatcat:h2uf6wvdnbdnvit7dj66xmudbi

Structural insight into the protein translocation channel

William M Clemons, Jean-François Ménétret, Christopher W Akey, Tom A Rapoport
2004 Current Opinion in Structural Biology  
doi:10.1016/ pmid:15313231 fatcat:mg46roeoerg3pnvsa3l25lbfxy

A comparison of the yeast and rabbit 80 S ribosome reveals the topology of the nascent chain exit tunnel, inter-subunit bridges and mammalian rRNA expansion segments 1 1Edited by W. Baumesiter

David Gene Morgan, Jean-François Ménétret, Michael Radermacher, Andrea Neuhof, Ildikó V Akey, Tom A Rapoport, Christopher W Akey
2000 Journal of Molecular Biology  
The tilted images corresponding to the largest class were processed to generate an initial low-resolution 3D volume using the random conical tilt procedure implemented in SPI-DER (Radermacher, 1988; Akey  ...  The sample was then applied to a 10 %-30 % linear sucrose gradient (10 %-30 % (w/v) sucrose, 10 mM BisTris (pH 6.5), 2 mM magnesium acetate, 100 mM potassium acetate, 2 mM DTT, 1:500 Solution P) and spun  ... 
doi:10.1006/jmbi.2000.3947 pmid:10926511 fatcat:ag4ujgzb5ne7hfbv7wbxzgirpi

Structure of the Drosophila Apoptosome at 6.9 Å Resolution

Shujun Yuan, Xinchao Yu, Maya Topf, Loretta Dorstyn, Sharad Kumar, Steven J. Ludtke, Christopher W. Akey
2011 Structure  
doi:10.1016/j.str.2010.10.009 pmid:21220123 pmcid:PMC3053581 fatcat:cg4a7uqeprf77kvaubmgcudnju

The Yeast Spindle Pole Body Is Assembled around a Central Crystal of Spc42p

Esther Bullitt, Michael P. Rout, John V. Kilmartin, Christopher W. Akey
1997 Cell  
Conserved Vertical Architecture Supramolecular assemblies are generally well preserved in the frozen-hydrated state, as they are subjected to minimal changes in buffer composition, pH, and surface tension (Akey  ...  array of a few proteins are anchored to the IL layers. by this organelle, because a precedent exists in the However, the pronounced hexagonal organization of the architecture of the nuclear pore complex (Akey  ... 
doi:10.1016/s0092-8674(00)80295-0 pmid:9215630 fatcat:sz7ned2qpja47mz5uw4jiccp4m
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