TY  - JOUR
A1  - Ni, Xiaomin
A1  - Knapp, Stefan
A1  - Chaikuad, Apirat
T1  - Comparative structural analyses and nucleotide-binding characterization of the four KH domains of FUBP1
T2  - Scientific reports
N2  - The FUBP1-FUSE complex is an essential component of a transcription molecular machinery that is necessary for tight regulation of expression of many key genes including c-Myc and p21. FUBP1 utilizes its four articulated KH modules, which function cooperatively, for FUSE nucleotide binding. To understand molecular mechanisms fundamental to the intermolecular interaction, we present a set of crystal structures, as well ssDNA-binding characterization of FUBP1 KH domains. All KH1-4 motifs were highly topologically conserved, and were able to interact with FUSE individually and independently. Nevertheless, differences in nucleotide binding properties among the four KH domains were evident, including higher nucleotide-binding potency for KH3 as well as diverse nucleotide sequence preferences. Variations in amino acid compositions at one side of the binding cleft responsible for nucleobase resulted in diverse shapes and electrostatic charge interaction, which might feasibly be a contributing factor for different nucleotide-binding propensities among KH1-4. Nonetheless, conservation of structure and nucleotide-binding property in all four KH motifs is essential for the cooperativity of multi KH modules present in FUBP1 towards nanomolar affinity for FUSE interaction. Comprehensive structural comparison and ssDNA binding characteristics of all four KH domains presented here provide molecular insights at a fundamental level that might be beneficial for elucidating the mechanisms of the FUBP1-FUSE interaction.
KW  - Biochemistry
KW  - Structural biology
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/79515
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-795154
SN  - 2045-2322
N1  - We are grateful for support by the SGC, a registered charity (number 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genome Canada, Innovative Medicines Initiative (EU/EFPIA) EUbOPEN (agreement No 875510), Janssen, Merck KGaA, Germany, MSD, Novartis Pharma AG, Ontario Ministry of Economic Development and Innovation, Pfizer, São Paulo Research Foundation-FAPESP, Takeda and Wellcome. We are grateful to the Stiftung Deutsche Krebshilfe for supporting the project: “Untersuchung und Inhibition der onkogenen Wirkung von FUBP1 in Heptatozellulären Karzinomen” (grant number: 70112344). The authors thank staffs at BESSY II and SLS for their support during crystallographic X-ray diffraction test and data collection. The data collection at SLS has been supported by the funding from the European Union’s Horizon 2020 research and innovation program under grant agreement number 730872, project CALIPSOplus. Open access funding provided by Projekt DEAL.
N1  - The coordinates and structure factors of all complexes have been deposited to the protein data bank under accession codes 6Y2D, 6Y2C and 6Y24.
VL  - 10
IS  - art. 13459
SP  - 1
EP  - 10
PB  - Macmillan Publishers Limited, part of Springer Nature
CY  - [London]
ER  -