What are Chimeric Proteins?

Chimeric proteins are fashioned through in vitro methodologies. Simply put, these chimeric proteins are a result of the fusion of chimeric genes through structural machinery (RNAs, rRNAs, tRNAs). Translation of these chimeric genes generates a single polypeptide chain, expressing different functionality from the original proteins from which it was derived.

Chimeric antigen receptor

Image Credit: Juan Gaertner/Shutterstock.com

Site-directed mutagenesis performed with certain expression vectors can allow for these gene fusions. With this genetic manipulation to create chimeric proteins, we can control the activity of many specified proteins, providing new insights into the field of therapeutics. In creating these expression vectors the target of regulation is often transcription.

Creating chimeric genes and chimeric proteins

To code for chimeric proteins, one must first construct the chimeric genes. The genes will then be transcribed from the DNA, resulting in mature mRNA that will then be translated into a cohesive polypeptide chain, forming our chimeric protein in question.

These fabricated chimeric genes often take the form of a plasmid or virus, an effective hull for gene manipulation. These chimeric genes can originate in two different ways. One is artificial, through two or more predetermined coding sequences. In contrast, some chimeric genes may result from errors in DNA replication or repair.

Specified chimeric proteins, if made artificially, are mostly used as therapeutic agents. These proteins are usually made of a peptide chain of <50 amino acids. They consist of a short-lived effector domain and a carrier that also contributes to the functional motifs of the resultant peptide chain. These two different protein domains work in unity to form a cohesive and functional chimeric protein.

For example, one peptide chain might have varying properties which could contribute to binding, recognition, or even toxicity, while its fused counterpart could aid in the targeting and stabilizing of the chimeric polypeptide.

An example of a chimeric gene, brought about by the joining of two or more genes that initially coded for separate proteins, are the Jingwei genes found in Drosophila. The chimeric protein that resulted from these genes was derived from a gene that codes for alcohol dehydrogenase, and the yellow emperor gene.

This new-fangled gene acts on long-chain alcohols and diols, such as pheromones and hormones, resulting in a direct change in the Drosophila’s fitness (ability to foster viable fertile offspring). After further studies accomplished by Long M et al., it was concluded that this amalgamation of different protein domains resulted in a more favored selection.

Harmful phenotypes brought about by chimeric proteins

Though improved fitness may prove true in the Jingwei et al. case study, the function of many chimeric genes/proteins are unknown and could even trigger diseases such as cancer or schizophrenia. Caution should also be exercised on account of an increased risk of infection due to opportunistic pathogens that come with chimeric fusion protein therapy.

Sepsis and tuberculosis are common diseases that may come consequently from these therapeutic agents. The TNF targeted mAb infliximab protein, for example, carries with it 3-4x the risk of infection compared to common etanercept therapy.

Chimeric genes may also form through retrotransposition, where RNA can be reverted to cDNA, accidentally causing the transcripts to insert themselves into the genome in unconventional locations. By these means, chimeric genes can sometimes form abnormal chimeric proteins that can cause color blindness or other ailments.

How chimeric genes propel evolution

Chimeric genes and their subsequent proteins can also occur in nature. They are a massive proponent of natural selection, the process by which favored inherited traits are passed on-altering the genetic makeup of generations over time.

Chimeric proteins are distinct from parental genes, resulting in entirely new phenotypes that would not have been possible under natural heredity. While some chimeric proteins might result in the termination of certain individuals, others can greatly increase fitness, spreading widely amongst new populations.

Chimeric proteins in medicine: Chimeric antigen receptor T cell therapy

One example of chimeric proteins being applied in medicine is chimeric antigen receptors; antibody proteins that are anchored to B-cell membranes. Also known as CAR-T cells, these cells have been genetically altered to produce designer T cell receptors. They are used in the fields of immunotherapy, immunology, and virology. The purpose of these chimeric receptor proteins is to grant altered T cells the ability to target specified proteins.

These antigen receptors are chimeric in nature because they are an amalgamation of antigen-binding, and T cell activating features. These antigen recognition domains stem from linked monoclonal antibodies, while the chimeric protein itself is made of chains of immunoglobins. These immunoglobins, connected through short linker peptides, have the ability to bind to target antigens such as CD19 and CD20.

In anticancer therapy, these chimeric proteins have been used to treat non-Hodgkin lymphoma and acute lymphoblastic leukemia. By inducing the dimerization of the human caspase 9 enzyme, these proteins can trigger an apoptosis signal from both the cancer cell and T cell.

By tuning the T cells so they recognize specific proteins, researchers have been able to train a patient’s own immune system to identify and eliminate their cancer cells. Though these chimeric proteins come with great boons and great cons, it is agreed that further research should be conducted on their nature and other therapeutic uses.

Sources:

  • Long M, Langley CH. (1993) Natural selection and the origin of jingwei, a chimeric processed functional gene in Drosophila. Science;260(5104):91-5
  • Ian I. Cardle, Emmeline L. Cheng, Michael C. Jensen, and Suzie H. Pun (2020) Biomaterials in Chimeric Antigen Receptor T-Cell Process Development. Accounts of Chemical Research 53 (9), 1724-1738
  • Antonella Antignani and Richard J. Youle. (2005) A Chimeric Protein Induces Tumor Cell Apoptosis by Delivering the Human Bcl-2 Family BH3-Only Protein Bad 44 (10), 4074-4082
  • Justin R. Klesmith, Lihe Su, Lan Wu, Ian A. Schrack, Fay J. Dufort, Alyssa Birt, Christine Ambrose, Benjamin J. Hackel, Roy R. Lobb, and Paul D. Rennert (2019). Retargeting CD19 Chimeric Antigen Receptor T Cells via Engineered CD19-Fusion Proteins. Molecular Pharmaceutics 16 (8), 3544-3558
  • Rippey, C., Walsh, T., Gulsuner, S., Brodsky, M., Nord, A. S., Gasperini, M., Pierce, S., Spurrell, C., Coe, B. P., Krumm, N., Lee, M. K., Sebat, J., McClellan, J. M., & King, M. C. (2013). Formation of chimeric genes by copy-number variation as a mutational mechanism in schizophrenia. American journal of human genetics, 93(4), 697–710.
  • Wen Wang, Jianming Zhang, Carlos Alvarez, Ana Llopart, Manyuan Long (2000). The Origin of the Jingwei Gene and the Complex Modular Structure of Its Parental Gene, Yellow Emperor, in Drosophila melanogaster, Molecular Biology and Evolution, Volume 17, Issue 9, Pages 1294–1301

Further Reading

Last Updated: Oct 21, 2021

Vasco Medeiros

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Vasco Medeiros

Obtaining an International Baccalaureate Degree at Oeiras International School, with higher levels in Chemistry, Biology, and Portuguese, Vasco Medeiros has just graduated from the University of Providence College with a Bachelor of Science. Before his work as an undergraduate, he first began his vocational training at the HIKMA Pharmaceuticals PLC plant in Ribeiro Novo. Here he worked as a validation specialist, tasked with monitoring the gauging and pressure equipment of the plant, as well as the inspection of weights and products.

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