ASCIZ, third C2HC zinc finger domain (Znf_C2HC_ASCIZ_3rd)
Type: Domain

This domain is found in the human ATM interactor (also known as ATM/ATR-substrate CHK2-interacting zinc finger protein (ASCIZ)) and related proteins from animals. These proteins are transcription factors that are essential for cell survival and the formation of RAD51 foci, a response to methylating DNA damage . They are also involved in the regulation of ATM (ataxia telangiectasia mutated) kinase activity, particularly in the absence of DNA damage, potentially by stabilising ATM . ASCIZ is predicted to contain four zinc finger domains. This entry represents the third zinc finger domain, which is a variant of the classical C2H2 zinc fingers bearing cysteine residue instead of histidine in the fourth zinc ligand position.

C2H2-type (classical) zinc fingers (Znf) were the first class to be characterised. They contain a short β-hairpin and an α-helix (β/β/α structure), where a single zinc atom is held in place by Cys(2)His(2) (C2H2) residues in a tetrahedral array. C2H2 Znf's can be divided into three groups based on the number and pattern of fingers: triple-C2H2 (binds single ligand), multiple-adjacent-C2H2 (binds multiple ligands), and separated paired-C2H2 . C2H2 Znf's are the most common DNA-binding motifs found in eukaryotic transcription factors, and have also been identified in prokaryotes . Transcription factors usually contain several Znf's (each with a conserved β/β/α structure) capable of making multiple contacts along the DNA, where the C2H2 Znf motifs recognise DNA sequences by binding to the major groove of DNA via a short α-helix in the Znf, the Znf spanning 3-4 bases of the DNA . C2H2 zinc fingers can also bind to RNA and protein targets .

Zinc finger (Znf) domains are relatively small protein motifs which contain multiple finger-like protrusions that make tandem contacts with their target molecule. Some of these domains bind zinc, but many do not; instead binding other metals such as iron, or no metal at all. For example, some family members form salt bridges to stabilise the finger-like folds. They were first identified as a DNA-binding motif in transcription factor TFIIIA from Xenopus laevis (African clawed frog), however they are now recognised to bind DNA, RNA, protein and/or lipid substrates . Their binding properties depend on the amino acid sequence of the finger domains and of the linker between fingers, as well as on the higher-order structures and the number of fingers. Znf domains are often found in clusters, where fingers can have different binding specificities. There are many superfamilies of Znf motifs, varying in both sequence and structure. They display considerable versatility in binding modes, even between members of the same class (e.g. some bind DNA, others protein), suggesting that Znf motifs are stable scaffolds that have evolved specialised functions. For example, Znf-containing proteins function in gene transcription, translation, mRNA trafficking, cytoskeleton organisation, epithelial development, cell adhesion, protein folding, chromatin remodelling and zinc sensing, to name but a few . Zinc-binding motifs are stable structures, and they rarely undergo conformational changes upon binding their target.