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Role for first zinc finger of WT1 in DNA sequence specificity: Denys-Drash syndrome-associated WT1 mutant in ZF1 enhances affinity for a subset of WT1 binding sites.

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Wang D, Horton JR, Zheng Y, Blumenthal RM, Zhang X, Cheng X
OpenAccess logo Nucleic Acids Res 46 3864-3877 (2018)
Related entries: 6b0o, 6b0p, 6b0q, 6blw

Cited: 12 times
EuropePMC logo PMID: 29294058

Abstract

Wilms tumor protein (WT1) is a Cys2-His2 zinc-finger transcription factor vital for embryonic development of the genitourinary system. The protein contains a C-terminal DNA binding domain with four tandem zinc-fingers (ZF1-4). An alternative splicing of Wt1 can add three additional amino acids-lysine (K), threonine (T) and serine (S)-between ZF3 and ZF4. In the -KTS isoform, ZF2-4 determine the sequence-specificity of DNA binding, whereas the function of ZF1 remains elusive. Three X-ray structures are described here for wild-type -KTS isoform ZF1-4 in complex with its cognate DNA sequence. We observed four unique ZF1 conformations. First, like ZF2-4, ZF1 can be positioned continuously in the DNA major groove forming a 'near-cognate' complex. Second, while ZF2-4 make base-specific interactions with one DNA molecule, ZF1 can interact with a second DNA molecule (or, presumably, two regions of the same DNA molecule). Third, ZF1 can intercalate at the joint of two tail-to-head DNA molecules. If such intercalation occurs on a continuous DNA molecule, it would kink the DNA at the ZF1 binding site. Fourth, two ZF1 units can dimerize. Furthermore, we examined a Denys-Drash syndrome-associated ZF1 mutation (methionine at position 342 is replaced by arginine). This mutation enhances WT1 affinity for a guanine base. X-ray crystallography of the mutant in complex with its preferred sequence revealed the interactions responsible for this affinity change. These results provide insight into the mechanisms of action of WT1, and clarify the fact that ZF1 plays a role in determining sequence specificity of this critical transcription factor.

Articles - 6b0r mentioned but not cited (2)

  1. Role for first zinc finger of WT1 in DNA sequence specificity: Denys-Drash syndrome-associated WT1 mutant in ZF1 enhances affinity for a subset of WT1 binding sites. Wang D, Horton JR, Zheng Y, Blumenthal RM, Zhang X, Cheng X. Nucleic Acids Res 46 3864-3877 (2018)
  2. Crystal structures of REF6 and its complex with DNA reveal diverse recognition mechanisms. Tian Z, Li X, Li M, Wu W, Zhang M, Tang C, Li Z, Liu Y, Chen Z, Yang M, Ma L, Caba C, Tong Y, Lam HM, Dai S, Chen Z. Cell Discov 6 17 (2020)


Reviews citing this publication (2)

  1. Disorder and cysteines in proteins: A design for orchestration of conformational see-saw and modulatory functions. Bhopatkar AA, Uversky VN, Rangachari V. Prog Mol Biol Transl Sci 174 331-373 (2020)
  2. Molecular update on biology of Wilms Tumor 1 gene and its applications in acute myeloid leukemia. Goel H, Rahul E, Gupta AK, Meena JP, Chopra A, Ranjan A, Hussain S, Rath GK, Tanwar P. Am J Blood Res 10 151-160 (2020)

Articles citing this publication (8)

  1. Structural basis of specific DNA binding by the transcription factor ZBTB24. Ren R, Hardikar S, Horton JR, Lu Y, Zeng Y, Singh AK, Lin K, Coletta LD, Shen J, Lin Kong CS, Hashimoto H, Zhang X, Chen T, Cheng X. Nucleic Acids Res 47 8388-8398 (2019)
  2. Influence of Disease-Causing Mutations on Protein Structural Networks. Prabantu VM, Naveenkumar N, Srinivasan N. Front Mol Biosci 7 620554 (2020)
  3. Large-Scale Analysis of Redox-Sensitive Conditionally Disordered Protein Regions Reveals Their Widespread Nature and Key Roles in High-Level Eukaryotic Processes. Erdős G, Mészáros B, Reichmann D, Dosztányi Z. Proteomics 19 e1800070 (2019)
  4. Enzymatic characterization of mRNA cap adenosine-N6 methyltransferase PCIF1 activity on uncapped RNAs. Yu D, Dai N, Wolf EJ, Corrêa IR, Zhou J, Wu T, Blumenthal RM, Zhang X, Cheng X. J Biol Chem 298 101751 (2022)
  5. LAHMA: structure analysis through local annotation of homology-matched amino acids. van Beusekom B, Damaskos G, Hekkelman ML, Salgado-Polo F, Hiruma Y, Perrakis A, Joosten RP. Acta Crystallogr D Struct Biol 77 28-40 (2021)
  6. Neural network modeling of differential binding between wild-type and mutant CTCF reveals putative binding preferences for zinc fingers 1-2. Kaplow IM, Banerjee A, Foo CS. BMC Genomics 23 295 (2022)
  7. Whole exome sequencing identified a rare WT1 loss-of-function variant in a non-syndromic POI patient. Wang Y, Chen Q, Zhang F, Yang X, Shang L, Ren S, Pan Y, Zhou Z, Li G, Fang Y, Jin L, Wu Y, Zhang X. Mol Genet Genomic Med 10 e1820 (2022)
  8. FBXO38 Ubiquitin Ligase Controls Centromere Integrity via ZXDA/B Stability. Dibus N, Korinek V, Cermak L. Front Cell Dev Biol 10 929288 (2022)


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