8eml | pdb_00008eml
Crystal Structure of Gsx2 Homeodomain in Complex with DNA
Structural highlights
FunctionGSX2_MOUSE Transcription factor that binds 5'-CNAATTAG-3' DNA sequence and regulates the expression of numerous genes including genes important for brain development (PubMed:7619729). During telencephalic development, causes ventralization of pallial progenitors and, depending on the developmental stage, specifies different neuronal fates. At early stages, necessary and sufficient to correctly specify the ventral lateral ganglionic eminence (LGE) and its major derivatives, the striatal projection neurons. At later stages, may specify LGE progenitors toward dorsal LGE fates, including olfactory bulb interneurons (PubMed:19709628).[1] [2] Publication Abstract from PubMedThe conserved Gsx homeodomain (HD) transcription factors specify neural cell fates in animals from flies to mammals. Like many HD proteins, Gsx factors bind A/T-rich DNA sequences prompting the following question: How do HD factors that bind similar DNA sequences in vitro regulate specific target genes in vivo? Prior studies revealed that Gsx factors bind DNA both as a monomer on individual A/T-rich sites and as a cooperative homodimer to two sites spaced precisely 7 bp apart. However, the mechanistic basis for Gsx-DNA binding and cooperativity is poorly understood. Here, we used biochemical, biophysical, structural and modeling approaches to (i) show that Gsx factors are monomers in solution and require DNA for cooperative complex formation, (ii) define the affinity and thermodynamic binding parameters of Gsx2/DNA interactions, (iii) solve a high-resolution monomer/DNA structure that reveals that Gsx2 induces a 20 degrees bend in DNA, (iv) identify a Gsx2 protein-protein interface required for cooperative DNA binding and (v) determine that flexible spacer DNA sequences enhance Gsx2 cooperativity on dimer sites. Altogether, our results provide a mechanistic basis for understanding the protein and DNA structural determinants that underlie cooperative DNA binding by Gsx factors. Cooperative Gsx2-DNA binding requires DNA bending and a novel Gsx2 homeodomain interface.,Webb JA, Farrow E, Cain B, Yuan Z, Yarawsky AE, Schoch E, Gagliani EK, Herr AB, Gebelein B, Kovall RA Nucleic Acids Res. 2024 Jul 22;52(13):7987-8002. doi: 10.1093/nar/gkae522. PMID:38874471[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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