A motif literally means a dominant element. Certain motifs in proteins mediate the binding of regulatory proteins or transcription factors to DNA. The specific control of transcription process occurs by the binding of regulatory proteins with high affinity to the specific regions of the DNA. Motifs are determined by structural or sequence alignments. Protein motifs consist of alpha helices and loops which connect in different arrangements to form different motifs.
A vast range of specific protein-DNA interactions occur due to the role of four unique and major motifs. The four major regulatory amino acid motifs are as follows.
• Helix-Turn-Helix (HTH)
• Zinc Finger
• Leucine Zipper
• Helix-Loop-Helix (HLH)
They bind to the specific site on the DNA with high affinity while they show low affinity towards other part of the DNA strand. Hydrogen bonds and Van der Waals forces play the main role in the motif-DNA interaction and binding.
A. Helix-Turn-Helix Motif
The Helix-Turn-Helix or HLH consists of around 20 amino acids, being around a tiny part of a large protein. HTH is the active part of the protein which plays the role of the domain part which specifically interacts with the DNA. HTH comprises of two alpha helices joined shortly by a short strand of amino acids which form the turn between the alpha helices. Helix turn helix motif forms of tertiary structure proteins. The alpha helices appear at the N-terminal and C-terminal of the motif. Interaction with the DNA is mainly controlled by the two alpha helices.
They recognise and bind to the DNA. The second alpha helix attaches to the DNA by binding through the major DNA groves whereas the first alpha helix binds DNA with proteins. The binding of the helix turn helix motif with the DNA strand is done by the hydrogen bonds and Van der Walls force. Examples of Helix-Turn-Helix motif proteins include lactose repressors and cyclic AMP catabolite activator protein or CAP of E.coli and several developmentally important transcription factors in mammals, collectively referred to as homeodomain proteins. Homeodomain proteins play a major role in development of mammals.
B. Zinc Finger Motif
Zinc finger motif is a small cluster of proteins that help to stabilize the folding of the protein structure. The transcription factor TFIIIA in transcription requires zinc for its activity. Zinc Finger motif comprises of a closely spaced repetitive complex of amino acids cysteine and cysteine followed by a histidine and histidine pair. Sometimes in some class of zinc finger motif Cys-Cys pair replaces the His-His pair.
The zinc finger motif binds to the major groove of the DNA. It binds to the DNA by making contact with a specific place in the DNA strand of 5 bp length. The steroid hormone receptor transcription factors use zinc finger motifs to bind to the DNA. Occurrence in a mutation in the zinc finger motif results in irregularity in gene expression.
C. Leucine Zipper Motif
The basic regions of leucine zipper motif consist of rich regions of amino acid leucine. There occurs a periodic repeat of leucine residues at every seventh position in every short alpha helix. The alpha helix is an amphipathic one with hydrophobic residues at one side. They are present in DNA binding transcription factors and they regulate the gene expression. This type of repetitive hydrophobic structures allows two identical monomers or heterodimers to zip together and form a dimeric complex.
This protein complex associates and interacts with DNA. Good examples of leucine zipper proteins are the enhancer binding proteins or EBP such as c-fos and c-jun. an irregularity in the leucine zipper motif which regulates the normal growth of an organism may results in a genetic cancer.
D. Helix-Loop-Helix Motif
Two amphipathic alpha helices form the helix loop helix or HLH motif. The alpha helices are connected by a loop. The alpha helices contain amino acids which favours binding to the DNA by dimerization between the alpha helices. The dimerization of the alpha helices is favoured as one helix is shorter than the other and the flexible loop allows them to join and form the dimer.
The larger alpha helix contains the region to bind to the DNA at a specific position. This specific position on the DNA is a consensus sequence called E-Box. HLH motif controls a number of regulatory pathways that control the developmental process.
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