High Resolution NMR Structure of the Wilms' Tumor Suppressor Protein (WT1) Finger 3
[WT1_HUMAN] Defects in WT1 are the cause of Frasier syndrome (FS) [MIM:136680]. FS is characterized by a slowly progressing nephropathy leading to renal failure in adolescence or early adulthood, male pseudohermaphroditism, and no Wilms tumor. As for histological findings of the kidneys, focal glomerular sclerosis is often observed. There is phenotypic overlap with Denys-Drash syndrome. Inheritance is autosomal dominant. Defects in WT1 are the cause of Wilms tumor 1 (WT1) [MIM:194070]. WT is an embryonal malignancy of the kidney that affects approximately 1 in 10'000 infants and young children. It occurs both in sporadic and hereditary forms.    Defects in WT1 are the cause of Denys-Drash syndrome (DDS) [MIM:194080]. DDS is a typical nephropathy characterized by diffuse mesangial sclerosis, genital abnormalities, and/or Wilms tumor. There is phenotypic overlap with WAGR syndrome and Frasier syndrome. Inheritance is autosomal dominant, but most cases are sporadic.                 Defects in WT1 are the cause of nephrotic syndrome type 4 (NPHS4) [MIM:256370]. A renal disease characterized clinically by proteinuria, hypoalbuminemia, hyperlipidemia and edema. Kidney biopsies show non-specific histologic changes such as focal segmental glomerulosclerosis and diffuse mesangial proliferation. Some affected individuals have an inherited steroid-resistant form and progress to end-stage renal failure. Most patients with NPHS4 show diffuse mesangial sclerosis on renal biopsy, which is a pathologic entity characterized by mesangial matrix expansion with no mesangial hypercellularity, hypertrophy of the podocytes, vacuolized podocytes, thickened basement membranes, and diminished patency of the capillary lumen.    Defects in WT1 are a cause of Meacham syndrome (MEACHS) [MIM:608978]. Meacham syndrome is a rare sporadically occurring multiple malformation syndrome characterized by male pseudohermaphroditism with abnormal internal female genitalia comprising a uterus and double or septate vagina, complex congenital heart defect and diaphragmatic abnormalities. Note=A chromosomal aberration involving WT1 may be a cause of desmoplastic small round cell tumor (DSRCT). Translocation t(11;22)(p13;q12) with EWSR1. Defects in WT1 may be a cause of mesothelioma malignant (MESOM) [MIM:156240]. An aggressive neoplasm of the serosal lining of the chest. It appears as broad sheets of cells, with some regions containing spindle-shaped, sarcoma-like cells and other regions showing adenomatous patterns. Pleural mesotheliomas have been linked to exposure to asbestos.
[WT1_HUMAN] Transcription factor that plays an important role in cellular development and cell survival. Regulates the expression of numerous target genes, including EPO. Plays an essential role for development of the urogenital system. Recognizes and binds to the DNA sequence 5'-CGCCCCCGC-3'. It has a tumor suppressor as well as an oncogenic role in tumor formation. Function may be isoform-specific: isoforms lacking the KTS motif may act as transcription factors. Isoforms containing the KTS motif may bind mRNA and play a role in mRNA metabolism or splicing. Isoform 1 has lower affinity for DNA, and can bind RNA. 
Publication Abstract from PubMed
The zinc finger, a motif of protein-nucleic acid recognition broadly conserved among eukaryotes, is a globular minidomain containing a tetrahedral metal-binding site. Preferential coordination of Zn(2+) (relative to Co(2+)) is proposed to reflect differences in ligand-field stabilization energies (LFSEs) due to complete or incomplete occupancy of d orbitals. LFSE predicts that the preference for Zn(2+) should be purely enthalpic in accord with calorimetric studies of a high-affinity consensus peptide (CP-1; Blasie, C. A., and Berg, J. (2002) Biochemistry 41, 15068-73). Despite its elegance, the general predominance of LFSE is unclear as (i) the magnitude by which CP-1 prefers Zn(2+) is greater than that expected and (ii) the analogous metal ion selectivity of a zinc metalloenzyme (carbonic anhydrase) is driven by changes in entropy rather than enthalpy. Because CP-1 was designed to optimize zinc binding, we have investigated the NMR structure and metal ion selectivity of a natural finger of lower stability derived from human tumor-suppressor protein WT1. Raman spectroscopy suggests that the structure of the WT1 domain is unaffected by interchange of Zn(2+) and Co(2+). As in CP-1, preferential binding of Zn(2+) (relative to Co(2+)) is driven predominantly by differences in enthalpy, but in this case the enthalpic advantage is less than that predicted by LFSE. A theoretical framework is presented to define the relationship between LFSE and other thermodynamic factors, such as metal ion electroaffinities, enthalpies of hydration, and the topography of the underlying folding landscape. The contribution of environmental coupling to entropy-enthalpy compensation is delineated in a formal thermodynamic cycle. Together, these considerations indicate that LFSE provides an important but incomplete description of the stringency and thermodynamic origin of metal-ion selectivity.
Why zinc fingers prefer zinc: ligand-field symmetry and the hidden thermodynamics of metal ion selectivity.,Lachenmann MJ, Ladbury JE, Dong J, Huang K, Carey P, Weiss MA Biochemistry. 2004 Nov 9;43(44):13910-25. PMID:15518539
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.