Oncogenic mutations in K-Ras CaM interactions

Husna, Amity University Kolkata

What is K-Ras-CaM interaction?

K-Ras is an oncogenic mutant that helps the cancer cells to proliferate, migrate, invade, and survive by assembling some signalling complexes. These complexes have a great therapeutic and mechanistic significance, however, to date, the functional and structural roles of K-Ras mutations within these complexes are not completely understood. K-Ras GTPase specifically binds to a calcium sensor known as calmodulin (CaM). This binding helps to regulate signal transduction in cancer and it remains the primary focus of intense research. 

Recent study: A 2021 study has reviewed recent advances to understand specific binding between K-Ras and calmodulin (calcium sensor). The review published in Current Opinion in Structural Biology has highlighted the key features of the interaction between wild-type K-Ras and calmodulin (CaM).

Insights into K-Ras-CaM interaction:

For the development of a proper signalling cascade, tight spatial and temporal regulation of proteins is highly essential. A ubiquitous regulator of many essential cellular signalling processes in health and disease is calmodulin (CaM). Calmodulin (CaM) is a small protein that is 148 amino acids long and it comprises two globular domains that are connected by a flexible linker. Each of the domains can bind two calcium ions. However, the calcium affinity of the N-terminal domain is lower in comparison to the C-terminal domain; this difference in affinity allows CaM’s conformations to adapt in response to changing calcium concentrations. Protein-protein complexes involving CaM are highly sensitive to environmental conditions and it depends on pH and concentrations of metal ions. 

So, the binding of CaM to other proteins can modulate signalling cascades. GTPases are one of these groups of proteins, they are a family of signal transduction proteins. CaM is able to bind to several members of this family, followed by controlling their signalling cascades in a disease-specific manner. Ras family of GTPases, particularly Kirsten Ras isoform B (K-Ras4B), are vital oncogenic proteins that drive the cancer of epithelial origin, such as pancreatic, lung, and colorectal malignancies. 

K-Ras lacks the ability to be palmitoylated; it is polybasic and its hypervariable region on C-terminal is carboxymethylated and farnesylated. So, these are the distinct features of K-Ras’s HVR, responsible for selective binding to CaM As the functions of K-Ras in cancer cells can directly be regulated by CaM so this interaction is a focus of intense research. 

Oncogenic mutations of K-Ras alter the nature of interaction with CaM:

Oncogenic mutations in K-Ras occur at position 12 which inhibits the hydrolysis of GTP and traps the enzyme in a constitutively active state. Due to oncogenic mutations, there is a differential preference of membrane components and distinct signalling pathways which can further modulate CaM’s ability to extract oncogenic K-Ras from the membrane. By using isothermal titration calorimetry, it was shown that farnesylation is unlikely to be the only essential requirement in the formation of the K-Ras/CaM complex and instead it might strengthen this interaction further and help to attain a physiologically relevant affinity of oncogenic K-Ras for CaM.

Significance of the study:

• Studies of calmodulin complexes (CaM) with oncogenic mutants of K-Ras can give insights into the invention of some novel regulatory mechanisms, especially in cancer.

• Insights into K-Ras/CaM interactions may help to design some selective drugs.

Also read: Reverse optogenetics tool using zebrafish

Reference:

1. Abdelkarim, H., Leschinsky, N., Jang, H., Banerjee, A., Nussinov, R., & Gaponenko, V. (2021). The dynamic nature of the K-Ras/calmodulin complex can be altered by oncogenic mutations. Current Opinion in Structural Biology, 71, 164–170. https://doi.org/10.1016/j.sbi.2021.06.008

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Author info:

Husna is an undergraduate student of BTech Biotechnology at Amity University Kolkata. She is a research enthusiast in Immunology and Immunotherapy but she has a keen interest in various other Bioscience subjects as well. She is constantly focused on improving her knowledge and laboratory skills through various internships. She is a Scientific content writer who has knowledge in diverse backgrounds of Biotechnology.

Publications:

• https://bioxone.in/news/worldnews/is-the-frequent-prescription-of-ppi-medicines-a-boon-or-a-bane/
• https://bioxone.in/news/worldnews/role-of-lysosomes-and-%CE%B1-synuclein-fibrils-in-protein-misfolding/