Structural Basis for Dimerization and DNA Binding of Transcription Factor FLI1

Hou, Caixia; Tsodikov, Oleg V.

doi:10.1021/acs.biochem.5b01121

Structural Basis for Dimerization and DNA Binding of Transcription Factor FLI1

Journal Article · Mon Nov 30 00:00:00 EST 2015 · Biochemistry

DOI:https://doi.org/10.1021/acs.biochem.5b01121· OSTI ID:1237759

Hou, Caixia ^[1]; Tsodikov, Oleg V. ^[1]

Univ. of Kentucky, Lexington, KY (United States)

FLI1 (Friend leukemia integration 1) is a metazoan transcription factor that is upregulated in a number of cancers. Additionally, rearrangements of the fli1 gene cause sarcomas, leukemias, and lymphomas. These rearrangements encode oncogenic transcription factors, in which the DNA binding domain (DBD or ETS domain) of FLI1 on the C-terminal side is fused to a part of an another protein on the N-terminal side. Such abnormal cancer cell-specific fusions retain the DNA binding properties of FLI1 and acquire non-native protein–protein or protein–nucleic acid interactions of the substituted region. As a result, these fusions trigger oncogenic transcriptional reprogramming of the host cell. Interactions of FLI1 fusions with other proteins and with itself play a critical role in the oncogenic regulatory functions, and they are currently under intense scrutiny, mechanistically and as potential novel anticancer drug targets. We report elusive crystal structures of the FLI1 DBD, alone and in complex with cognate DNA containing a GGAA recognition sequence. Both structures reveal a previously unrecognized dimer of this domain, consistent with its dimerization in solution. The homodimerization interface is helix-swapped and dominated by hydrophobic interactions, including those between two interlocking Phe362 residues. A mutation of Phe362 to an alanine disrupted the propensity of this domain to dimerize without perturbing its structure or the DNA binding function, consistent with the structural observations. We propose that FLI1 DBD dimerization plays a role in transcriptional activation and repression by FLI1 and its fusions at promoters containing multiple FLI1 binding sites.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE; University of Kentucky

OSTI ID:: 1237759

Journal Information:: Biochemistry, Journal Name: Biochemistry Journal Issue: 50 Vol. 54; ISSN 0006-2960

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Crystal structure
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Structural Basis for Dimerization and DNA Binding of Transcription Factor FLI1

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References (54)

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