Zinc finger structure-function in Ikaros Marvin A Payne

Abstract

The zinc finger motif was used as a vehicle for the initial discovery of Ikaros in the context of T-cell differentiation and has been central to all subsequent analyses of Ikaros function. The Ikaros gene is alternately spliced to produce several isoforms that confer diversity of function and consequently have complicated analysis of the function of Ikaros in vivo. Key features of Ikaros in vivo function are associated with six C2H2 zinc fingers; four of which are alternately incorporated in the production of the various Ikaros isoforms. Although no complete structures are available for the Ikaros protein or any of its family members, considerable evidence has accumulated about the structure of zinc fingers and the role that this structure plays in the functions of the Ikaros family of proteins. This review summarizes the structural aspects of Ikaros zinc fingers, individually, and in tandem to provide a structural context for Ikaros function and to provide a structural basis to inform the design of future experiments with Ikaros and its family members.

Keywords: C2H2; DNA binding protein; Ikaros; Tandem; Transcription factor IIIA; Zinc finger.

Figure 1

Architecture of the Ikaros protein. The full-length Ikaros is shown in context of the exons present in the longest form of Ikaros. The positions of the six zinc fingers are shown in their approximate locations. Fingers 1-4 are contiguous as well as fingers 5 and 6.

Figure 2

Primary sequence of the six zinc fingers of Ikaros. The sequences of the six zinc fingers of human Ikaros are shown along with their respective linkers (UniProt: gi|3913926). The letters in red are the consensus Cys and His residues that chelate zinc in the fingers. The blue highlighted letters represent the -1, 2, 3, and 6 positions of the finger helices read from left to right.

Figure 3

Structure of an engineered peptide with three tandem zinc fingers similar to Ikaros ZF2-3. The views shown are from 1MEY (pdb), an engineered three tandem zinc finger peptide (shown in red) in complex with cognate DNA[4] shown in green. All three fingers show the zinc (grey sphere) complexed to two sulfurs of cysteine (yellow) and two imidazole nitrogen (blue). A: An overview of the zinc fingers nestled in the major groove of the DNA. The N terminus is on the left. The C-terminal finger has the DNA-interacting side chains shown; B: A view of the N-terminal finger showing the seven essential residues for zinc finger structural integrity; C: A view of the DNA-interacting residues on the C-terminal finger, -1:arg, 2:asp, 3:his, 6:arg. The views were produced using CHIMERA[35].