The Importance of Being Flexible: The Case of Basic Region Leucine Zipper Transcriptional Regulators

Large volumes of protein sequence and structure data acquired by proteomic studies led to the development of computational bioinformatic techniques that made possible the functional annotation and structural characterization of proteins based on their primary structure. It has become evident from genome-wide analyses that many proteins in eukaryotic cells are either completely disordered or contain long unstructured regions that are crucial for their biological functions. The content of disorder increases with evolution indicating a possibly important role of disorder in the regulation of cellular systems. Transcription factors are no exception and several proteins of this class have recently been characterized as premolten/molten globules. Yet, mammalian cells rely on these proteins to control expression of their 30,000 or so genes. Basic region: leucine zipper (bZIP) DNA-binding proteins constitute a major class of eukaryotic transcriptional regulators. This review discusses how conformational flexibility “built” into the amino acid sequence allows bZIP proteins to interact with a large number of diverse molecular partners and to accomplish their manifold cellular tasks in a strictly regulated and coordinated manner.

Keywords: bZIP proteins, transcription control, intrinsic disorder, sequence analysis, disorder predictors, natively-unfolded proteins, partially folded proteins, induced protein folding, molecular recognition motifs, protein-protein interactions, protein-DNA interactions, transient interactions, binding affinity, binding specificity, protein functional domains, bZIP oligomerization, combinatorial gene regulation, transcription coregulator complexes, cellulat networks, signaling.