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

Abstract

Members of the human Zyxin family are LIM domain-containing proteins that perform critical cellular functions and are indispensable for cellular integrity. Despite their importance, not much is known about their structure, functions, interactions and dynamics. To provide insights into these, we used a set of in-silico tools and databases and analyzed their amino acid sequence, phylogeny, post-translational modifications, structure-dynamics, molecular interactions, and functions. Our analysis revealed that zyxin members are ohnologs. Presence of a conserved nuclear export signal composed of LxxLxL/LxxxLxL consensus sequence, as well as a possible nuclear localization signal, suggesting that Zyxin family members may have nuclear and cytoplasmic roles. The molecular modeling and structural analysis indicated that Zyxin family LIM domains share similarities with transcriptional regulators and have positively charged electrostatic patches, which may indicate that they have previously unanticipated nucleic acid binding properties. Intrinsic dynamics analysis of Lim domains suggest that only Lim1 has similar internal dynamics properties, unlike Lim2/3. Furthermore, we analyzed protein expression and mutational frequency in various malignancies, as well as mapped protein-protein interaction networks they are involved in. Overall, our comprehensive bioinformatic analysis suggests that these proteins may play important roles in mediating protein-protein and protein-nucleic acid interactions.

Genome-Wide Phylogenetic Analysis, Expression Pattern, and Transcriptional Regulatory Network of the Pig C/EBP Gene Family

“…These results indicate that some C/EBP genes have low functional conservation among different eukaryotes. 47 , 48 …”

Lin11-Isl1-Mec3 Domain Proteins as Mechanotransducers in Endothelial and Vascular Smooth Muscle Cells

“…Moreover, zyxin contains four ActA repeats that serve as vasodilator-stimulated phosphoprotein (VASP) binding sites and one nuclear export signal (NES) between this VASP-binding region and the LIM domains (Figure 2). The nuclear export signal seems to be conserved among all zyxin family members (Siddiqui et al, 2021). There is a minor difference in the structure of the LPP protein compared to zyxin in this region in that LPP harbors only two ActA repeats, that is, VASP interaction domains, and that the single NES is located just distal to the ActA repeats rather than proximal to the first LIM domain, as in zyxin.…”

“…While both zyxin and LPP play an important role in regulation of the cytoskeletal organization, bioinformatic analyses of structural data suggest that all members of the zyxin family share similarities with transcriptional regulators (Siddiqui et al, 2021), indicating that these cytoskeletal regulators may perceive the mechanical stimulation at FA and relay this information to the nucleus, presumably by different means, to accordingly affect gene expression and cellular phenotype.…”

“…This is mediated by the two LIM domains and the proline-rich region (Petit et al, 2000). Upon exposure of cells to biomechanical deformation, LPP only transiently translocates to the nucleus where it may exhibit some transactivation capacity or function as a transcriptional co-activator to mediate the adaptive changes in gene expression in response to mechanical stress (Siddiqui et al, 2021). When the nuclear export sequence is removed or the nuclear export signal CRM1 is inhibited, LPP accumulates in the nucleus (Petit et al, 2000), emphasizing the nuclear-cytoplasmic shuttling role of LPP.…”

Dynamics and recognition of homeodomain containing protein-DNA complex of IRX4

“…Interpretation of mutants and their association to diseases can be significantly influenced using this technique 34 . A recent modelling study in the zyxin family of proteins LIM1-3 domains has indicated new insights into protein-protein interactions and potential nucleic acid binding platforms of these proteins, highlighting opportunities for therapeutic development 35 .…”