Ras isoform-specific expression, chromatin accessibility, and signaling

Abstract

The anchorage of Ras isoforms in the membrane and their nanocluster formations have been studied extensively, including their detailed interactions, sizes, preferred membrane environments, chemistry, and geometry. However, the staggering challenge of their epigenetics and chromatin accessibility in distinct cell states and types, which we propose is a major factor determining their specific expression, still awaits unraveling. Ras isoforms are distinguished by their C-terminal hypervariable region (HVR) which acts in intracellular transport, regulation, and membrane anchorage. Here, we review some isoform-specific activities at the plasma membrane from a structural dynamic standpoint. Inspired by physics and chemistry, we recognize that understanding functional specificity requires insight into how biomolecules can organize themselves in different cellular environments. Within this framework, we suggest that isoform-specific expression may largely be controlled by the chromatin density and physical compaction, which allow (or curb) access to “chromatinized DNA.” Genes are preferentially expressed in tissues: proteins expressed in pancreatic cells may not be equally expressed in lung cells. It is the rule—not an exception, and it can be at least partly understood in terms of chromatin organization and accessibility state. Genes are expressed when they can be sufficiently exposed to the transcription machinery, and they are less so when they are persistently buried in dense chromatin. Notably, chromatin accessibility can similarly determine expression of drug resistance genes.

Computational Analysis of Deleterious SNPs in NRAS to Assess Their Potential Correlation With Carcinogenesis

“…Furthermore, the InterPro server was used to identify the locations of these SNPs on NRAS protein domains, and the analysis found that all SNPs, except rs1658971260 SNP, were located on the important, small GTP-binding protein domain. This domain is responsible for catalytic activity and contains sites of nucleotide binding and effector interactions ( Omerovic et al, 2007 ; Nussinov et al, 2021 ). Therefore, mutations in this region are expected to affect the protein function and its binding properties.…”

Clinical Relevance of Secreted Small Noncoding RNAs in an Embryo Implantation Potential Prediction at Morula and Blastocyst Development Stages

“…Titin (TTN), a connectin, is megadalton-sized filamentous molecule that promotes human trophoblast invasiveness via the activation of the MAPK pathway, providing proper placentation and embryo development [42]. NRAS belongs to the family of Ras proteins, which control cell proliferation pathways, cell growth, and division [43]. Tropomodulin-3 (Tmod3) negatively regulates cell motility by controlling actin polymerization and stability, and in the case of Tmod3 knockdown, the gradual increase in the level of cytoplasmic actin and spin- It is important to note that the protein products of several analyzed target genes are polyfunctional, i.e., they participate in more than one biological process indicated in Figure 12.…”

Neurodevelopmental disorders, immunity, and cancer are connected

“…Owing to sparseness of data, such single cell transcriptomics are technically highly challenging; entries are missing, and they are noisy. Structural networks may not be able to distinguish between isoforms whose sequences (thus structures) are highly similar, yet have different functions, as discussed earlier for Rac1 versus Rac3, or K-Ras4B versus e.g., N-Ras or H-Ras, or splice isoform K-Ras4A ( Muratcioglu et al., 2017 ; Nussinov et al., 2016a ; Nussinov et al., 2021e ), or Rap1A versus Rap1B ( Nussinov et al., 2020 ). Posttranslational modification, degradation, and other forms of regulation are also important factors.…”