Bioinformatic Analysis of Structure and Function of LIM Domains of Human Zyxin Family Proteins

Abstract

Lim domains are one of the most abundant types of zinc-finger domains and are linked with diverse cellular functions ranging from cytoskeleton maintenance to gene regulation. Zyxin family Lim domains perform the critical cellular functions and are indispensable for cellular integrity. Despite having these important functions the fundamental nature of the sequence, structure, functions, and interactions of the Zyxin family Lim domains are largely unknown. Therefore, we have used a set ofin-silicotools and bioinformatics databases to distill the fundamental properties of the Zyxin family proteins/Lim domains from their amino acid sequence, phylogeny, biochemical analysis, post-translational modifications, structure-dynamics, molecular interactions, and functions. Consensus analysis of the nuclear export signal suggests a conserved Leucine-rich motif composed of LxxLxL/LxxxLxL. Molecular modeling and structural analysis demonstrate that Lim domains of the members of the Zyxin family proteins share similarities with transcriptional regulators, suggesting they could interact with nucleic acids as well. Normal mode, Covariance, and Elastic Network Model analysis of Zyxin family Lim domains suggest only the Lim1 region has similar internal dynamics properties, compared to Lim2/3. Protein expression/mutational frequency studies of the Zyxin family demonstrated higher expression and mutational frequency rates in various malignancies. Protein-protein interactions indicate that these proteins could facilitate metabolic rewiring and oncogenic addiction paradigm. Our comprehensive analysis of the Zyxin family proteins indicates that the Lim domains function in a variety of ways and could be implicated in rational protein engineering and might lead as a better therapeutic target for various diseases, including cancers.