TY  - JOUR
A1  - Hagen, Sven
A1  - Mattay, Dinah
A1  - Raeuber, Christina
A1  - Mueller, Kristian M.
A1  - Arndt, Katja Maren
T1  - Characterization and inhibition of AF10-mediated interaction
JF  - Journal of peptide science
N2  - The non-random chromosomal translocations t(10;11)(p13;q23) and t(10;11)(p13;q14-21) result in leukemogenic fusion proteins comprising the coiled coil domain of the transcription factor AF10 and the proteins MLL or CALM, respectively, and subsequently cause certain types of acute leukemia. The AF10 coiled-coil domain, which is crucial for the leukemogenic effect, has been shown to interact with GAS41, a protein previously identified as the product of an amplified gene in glioblastoma. Using sequential synthetic peptides, we mapped the potential AF10/GAS41 interaction site, which was subsequently be used as scaffold for a library targeting the AF10 coiled-coil domain. Using phage display, we selected a peptide that binds the AF10 coiled-coil domain with higher affinity than the respective coiled-coil region of wild-type GAS41, as demonstrated by phage ELISA, CD, and PCAs. Furthermore, we were able to successfully deploy the inhibitory peptide in a mammalian cell line to lower the expression of Hoxa genes that have been described to be overexpressed in these leukemias. This work dissects molecular determinants mediating AF10-directed interactions in leukemic fusions comprising the N-terminal parts of the proteins MLL or CALM and the C-terminal coiled-coil domain of AF10. Furthermore, it outlines the first steps in recognizing and blocking the leukemia-associated AF10 interaction in histiocytic lymphoma cells and therefore, may have significant implications in future diagnostics and therapeutics. Copyright (c) 2014 European Peptide Society and John Wiley & Sons, Ltd.
KW  - protein-protein interaction
KW  - protein design and selection
KW  - protein engineering
KW  - coiled coil
KW  - leucine zipper
KW  - AF10
Y1  - 2014
U6  - https://doi.org/10.1002/psc.2626
SN  - 1075-2617
SN  - 1099-1387
VL  - 20
IS  - 6
SP  - 385
EP  - 397
PB  - Wiley-Blackwell
CY  - Hoboken
ER  -