Andrew J. McCluskey
Harvard University
Protein subunitImmunotoxinFusion proteinElongation factorAntigenAntibodyPeptide sequencePseudomonas exotoxinChemistryEEF2Diphtheria toxinRibosomal proteinAnthrax toxinCancer researchPlasma protein bindingBiochemistryC-terminusRibosomal RNABiologyCell biologyCancer cell
Publications 11
#1Sherwin Jack (Purdue University)H-Index: 1
#2Kayalvizhi Madhivanan (Purdue University)H-Index: 6
Last. Ruben C. Aguilar (Purdue University)H-Index: 20
view all 21 authors...
: Bladder cancer is the sixth most common cancer in the United States, and it exhibits an alarming 70% recurrence rate. Thus, the development of more efficient antibladder cancer approaches is a high priority. Accordingly, this work provides the basis for a transformative anticancer strategy that takes advantage of the unique characteristics of the bladder. Unlike mucin-shielded normal bladder cells, cancer cells are exposed to the bladder lumen and overexpress EGFR. Therefore, we used an EGF-co...
6 CitationsSource
#1Elena Del Tordello (Harvard University)H-Index: 9
#2Olga Danilchanka (Harvard University)H-Index: 15
Last. John J. Mekalanos (Harvard University)H-Index: 129
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The bacterial type 6 secretion system (T6SS) is a dynamic apparatus that translocates proteins between cells by a mechanism analogous to phage tail contraction. T6SS sheaths are cytoplasmic tubular structures composed of stable VipA-VipB (named for ClpV-interacting protein A and B) heterodimers. Here, the structure of the VipA/B sheath was exploited to generate immunogenic multivalent particles for vaccine delivery. Sheaths composed of VipB and VipA fused to an antigen of interest were purified ...
9 CitationsSource
#1Chiranjib Ghatak (KU: University of Kansas)H-Index: 22
#2Mykola V. Rodnin (University of Kansas Hospital)H-Index: 14
Last. Alexey S. Ladokhin (University of Kansas Hospital)H-Index: 35
view all 7 authors...
The pH-triggered membrane insertion of the diphtheria toxin translocation domain (T domain) results in transferring the catalytic domain into the cytosol, which is relevant to potential biomedical applications as a cargo-delivery system. Protonation of residues is suggested to play a key role in the process, and residues E349, D352 and E362 are of particular interest because of their location within the membrane insertion unit TH8–TH9. We have used various spectroscopic, computational and functi...
12 CitationsSource
#1Erin L. Boland (WSU: Washington State University)H-Index: 3
#2Crystal M. Van Dyken (WSU: Washington State University)H-Index: 1
Last. Gregory M.K. Poon (WSU: Washington State University)H-Index: 20
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Abstract The catalytic moiety of Pseudomonas exotoxin A (domain III or PE3) inhibits protein synthesis by ADP-ribosylation of eukaryotic elongation factor 2. PE3 is widely used as a cytocidal payload in receptor-targeted protein toxin conjugates. We have designed and characterized catalytically inactive fragments of PE3 that are capable of structural complementation. We dissected PE3 at an extended loop and fused each fragment to one subunit of a heterospecific coiled coil. In vitro ADP-ribosyla...
4 CitationsSource
#1McCluskey Aj (Harvard University)H-Index: 1
#1Andrew J. McCluskey (Harvard University)H-Index: 8
Last. R. John Collier (Harvard University)H-Index: 63
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Chimeric protein toxins that act selectively on cells expressing a designated receptor may serve as investigational probes and/or antitumor agents. Here, we report use of the enzyme sortase A (SrtA) to create four chimeric toxins designed to selectively kill cells bearing the tumor marker HER2. We first expressed and purified: (i) a receptor recognition-deficient form of diphtheria toxin that lacks its receptor-binding domain and (ii) a mutated, receptor-binding–deficient form of anthrax-protect...
33 CitationsSource
#1Andrew J. McCluskey (Harvard University)H-Index: 8
#2Andrew J. Olive (Harvard University)H-Index: 22
Last. R. John Collier (Harvard University)H-Index: 63
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Targeted therapeutics have emerged in recent years as an attractive approach to treating various types of cancer. One approach is to modify a cytocidal protein toxin to direct its action to a specific population of cancer cells. We created a targeted toxin in which the receptor-binding and pore-forming moiety of anthrax toxin, termed Protective Antigen (PA), was modified to redirect its receptor specificity to HER2, a marker expressed at the surface of a significant fraction of breast and ovaria...
40 CitationsSource
#1Adva Mechaly (Harvard University)H-Index: 1
#2Andrew J. McCluskey (Harvard University)H-Index: 8
Last. R. John Collier (Harvard University)H-Index: 63
view all 3 authors...
The actions of many bacterial toxins depend on their ability to bind to one or more cell-surface receptors. Anthrax toxin acts by a sequence of events that begins when the protective-antigen (PA) moiety of the toxin binds to either one of two cell-surface proteins, ANTXR1 and ANTXR2, and is proteolytically activated. The activated PA self-associates to form oligo- meric pore precursors, which, in turn, bind the enzymatic moieties of the toxin and transport them to the cytosol. We intro- duced a ...
40 CitationsSource
#1Andrew J. McCluskey (U of T: University of Toronto)H-Index: 8
#2Eleonora Bolewska-Pedyczak (Sunnybrook Research Institute)H-Index: 4
Last. Jean Gariépy (U of T: University of Toronto)H-Index: 33
view all 6 authors...
Shiga-like toxins are ribosome-inactivating proteins (RIP) produced by pathogenic E. coli strains that are responsible for hemorrhagic colitis and hemolytic uremic syndrome. The catalytic A1 chain of Shiga-like toxin 1 (SLT-1), a representative RIP, first docks onto a conserved peptide SD[D/E]DMGFGLFD located at the C-terminus of all three eukaryotic ribosomal stalk proteins and halts protein synthesis through the depurination of an adenine base in the sarcin-ricin loop of 28S rRNA. Here, we rep...
30 CitationsSource
#1Andrew J. McCluskey (U of T: University of Toronto)H-Index: 8
#2Gregory M.K. Poon (UHN: University Health Network)H-Index: 20
Last. Jean Gariépy (U of T: University of Toronto)H-Index: 33
view all 7 authors...
Shiga-like toxin 1 (SLT-1) is a type II ribosome-inactivating protein; its A1 domain blocks protein synthesis in eukaryotic cells by catalyzing the depurination of a single adenine base in 28 S rRNA. The molecular mechanism leading to this site-specific depurination event is thought to involve interactions with eukaryotic ribosomal proteins. Here, we present evidence that the A1 chain of SLT-1 binds to the ribosomal proteins P0, P1, and P2. These proteins were identified from a HeLa cell lysate ...
68 CitationsSource