Structural determinants of specific DNA-recognition by the THAP zinc finger

Abstract

Human THAP1 is the prototype of a large family of cellular factors sharing an original THAP zinc-finger motif responsible for DNA binding. Human THAP1 regulates endothelial cell proliferation and G1/S cell-cycle progression, through modulation of pRb/E2F cell-cycle target genes including rrm1. Recently, mutations in THAP1 have been found to cause DYT6 primary torsion dystonia, a human neurological disease. We report here the first 3D structure of the complex formed by the DNA-binding domain of THAP1 and its specific DNA target (THABS) found within the rrm1 target gene. The THAP zinc finger uses its double-stranded β-sheet to fill the DNA major groove and provides a unique combination of contacts from the β-sheet, the N-terminal tail and surrounding loops toward the five invariant base pairs of the THABS sequence. Our studies reveal unprecedented insights into the specific DNA recognition mechanisms within this large family of proteins controlling cell proliferation, cell cycle and pluripotency.

A Transcriptional Regulatory Role of the THAP11–HCF-1 Complex in Colon Cancer Cell Function

“…This mutual interdependence of HCF-1 and a sequence-specific transcription factor has not been described previously and may represent a unique feature of THAP11. Recent structural analyses of prototypical THAP domains bound to their respective DNA elements have revealed that THAP proteins bind DNA in a bipartite manner, making simultaneous major-and minor-groove DNA contacts (5,35). Nonspecific contacts with the sugar-phosphate backbone of the minor groove are critical for THAP domain binding to DNA and are mediated primarily by basic amino acids present in a flexible loop structure positioned between the zinc-coordinating residues and the conserved AVPTIF box.…”

“…THAP domains are approximately 80 to 90 amino acids in length and, in addition to zinc-coordinating residues, contain several conserved or invariant residues necessary for proper domain folding and DNA-binding activity (4,5,7,35). The majority of conserved THAP proteins also contain a coiled-coil protein interaction domain adjacent to a host cell factor 1 (HCF-1)-binding motif (HBM) (26).…”

“…he Thanatos-associated protein (THAP) domain is an evolutionarily conserved C2-CH (C-X 2-4 -C-X 35-50 -C-X 2 -H) zinc finger motif with sequence-specific DNA-binding activity (5,(33)(34)(35). Twelve THAP proteins, each containing an N-terminally located THAP domain, have been identified in humans (THAP0 to THAP11), and a subset of these (THAP0, -1, -2, -4, -7, and -11) are also conserved in mice and rats (7).…”

Identification and functional analysis of novel THAP1 mutations

“…This finding is supported by three additional notions: first, the amino acids isoleucine and valine have a similar structure and both belong to the unpolar amino acids. Second, Campagne et al 21 revealed lysine 70 as the most C-terminal amino acid residue responsible for DNA binding by detailed structural determination of the THAP domain. Thus, isoleucine 80 should not be involved in DNA binding.…”

Study of the genetic basis of dystonia in Serbian population

“…Pretpostavlja se da bi THAP proteini preko coiledcoil domena mogli da posreduju u proteinskim interakcijama. Pokazano je da monomer THAP1 proteina ima nizak afinitet vezivanja za DNK (Campagne at al., 2010) i da in vivo THAP1 verovatno funkcioniše kao homodimer u okviru nekog većeg multimernog DNKvezujućeg kompleksa (Sengel et al, 2011). Slika 4.…”