Comparison of the Structure Between the Wild Type Lamin A/C Protein and the Cardiac Disease Causing Variant D192G

The lamin A/C (LMNA) gene codes for A type lamins which are key components of the nuclear lamina and are involved in maintaining the structure of the nucleus and its processes. Mutations in LMNA cause a group of diseases known as laminopathies. For this project, the lamin A/C variant affecting amino acid 192 is studied. The causal mutation results in an amino acid change from glycine [G] (smaller, non‐polar, uncharged) to aspartic acid [D] (larger, polar, charged). This D192G variant is linked to a severe form of a cardiac disease called Dilated Cardiomyopathy (DCM), where cardiomyocytes are presented with multiple nuclear abnormalities. In vitro experiments with the D192G variant showed abnormal nuclear localization of Protein Kinase C alpha (PKC‐α). PKC‐α is the major protein kinase C isoform found in the heart and skeletal muscles. This enzyme phosphorylates a host of proteins and uses A‐type lamins to reach its nuclear targets. In order to help elucidate the potential role of PKC‐α as the link between the disease phenotype and lamin mutation, a structural comparison between the wild type lamin A and the D192G variant was performed in silico. Moreover, the PKC‐α binding site on the wild type and mutant lamin A were compared in order to determine if a conformation change has occurred. Since there is currently no full‐length crystal structure for either the wild type or D192G lamin A/C variant, the I‐TASSER software suite was used to generate simulated protein structures. The top five structures for the WT and variant simulations were examined. The final models selected to most likely represent reality were chosen based on various factors such as computed C‐score, what is known in literature and human analysis of the simulations. The results show that the D192G variant predominantly takes a globular form which is very comparable to the structure of the wild type lamin A found in the nucleoplasm. This globular form also potentially explains the lamin aggregates found in cells expressing the D192G variant. However, this globular variant conformation significantly differs when compared to the known and prevalent wild type lamin A conformation which is the globular head‐alpha helical rod‐globular tail structure. In particular, the conformation of PKCα binding site on lamin A is also significantly altered. The Ashbury College MSOE Center for BioMolecular Modeling SMART Team used 3‐D modeling and printing technology to examine the structure‐function relationships of the wild type lamin A/C protein and the D192G variant.