Sequence-specific interactions of minor groove binders with the 154 base pair HindIII-RsaI restriction fragment of cDNA of the human Tau 40 protein involved in pathology of Alzheimer's disease

Kittler, L.; Matesoi, D.; Bell, A.; Baguley, B.C.; Unger, E.; Löber, G.

Biochemistry and Molecular Biology International 41(1): 143-152


ISSN/ISBN: 1039-9712
PMID: 9043643
Accession: 009400380

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The DNA minor groove binders netropsin, distamycin and four structurally related bisquaternary ammonium heterocycles (BQA), SN 6999, SN 6570, SN 6132 and SN 6131, were investigated for sequence-specific interactions with the 154 base pair fragment of cDNA of the human Tau 40 protein (h Tau 40 protein), involved in pathology of Alzheimer's disease. The base sequences 5' AATCTT 3', 5' AATATT 3' and 5' TTTCAATCTTTTTATTT 3' were identified as ligand specific binding sites and demonstrate the obvious dA cntdot dT binding preference. Footprinting titration experiments were performed to estimate sequence-specific binding constants (K-A). The K-A-values were in the order of 10-6M-1 and dependent on DNA base sequence as well as ligands used. The highest values estimated were for netropsin (K-A = 5.0 x 10-6M-1) and the quinoline derivative SN 6999 (K-A = 6.2 times 10-6M-1) binding to the sequence 5' ATAAT 3'. Microscopic binding constants are determined by the base sequence rather than by the length of dA cntdot dT stretches. In the extended dA cntdot dT run, 5' TTTCAATCTTTTTATTT 3', netropsin and distamycin binding tolerates the presence of two dG cntdot dC base pairs, as indicated by nearly unaffected footprints. In contrast, the failure of BQAs to form footprints demonstrates their significantly decreased binding selectivity.