LARPs in treatment of Fibrosis

LARPs or La- related proteins, are a superfamily of proteins present on both plants and animals.

What is LARP6? LARP6 is a crucial RNA-binding protein. The key function of this particular protein is it regulates type I collagen synthesis by binding to the 5’ stem-loop structure on collagen mRNAs.

Histology findings of skin biopsy showing extensive fibrosis with dense subepithelial collagen deposition, sparse inflammatory cell infiltration (black arrow), and entrapment of the dermal adnexa between the collagen fibers (white arrow) (a, b). Atrophy of the epidermis and loss of epidermal papilla (c) (H&E stain ×10).

Ref. Nakalema G, Egesa WI, Kumbakulu PK, et al. Sclerema neonatorum in a term infant: a case report and literature review. Case Rep Pediatr. 2020;2020:8837064. https://doi.org/10.1155/2020/8837064.

Researchers at Florida State University’s Institute of Molecular Biophysics and Department of Chemistry and Biochemistry have uncovered how a protein in the human body interacts with RNA that a discovery that could pave the way for new treatments for tissue scarring, also known as fibrosis (where too much collagen is made). The studied said that a special protein called LARP6, which plays a role in how the human body produce type I collagen. And this collagen is a vital building block of tissues such as skin and bones. The researchers identified a previously unknown part of the protein that allows it to recognize and bind to RNA with remarkable precision, much like two puzzle pieces fitting together. This study provides scientists with a clearer understanding of how LARP6 could be targeted in treatments for diseases caused by excessive collagen production.

“In the simplest terms, we’re trying to figure out how two molecules, just like LEGO pieces, fit together,” said principal investigator Robert Silvers, an assistant professor in the Department of Chemistry and Biochemistry. “But it’s obviously much more complicated than that, because we’re not just considering the structure of the LEGO pieces and how they fit together, but also how different parts of the LEGO pieces move around, and that all ties directly into functionality.” The team was introduced to this unusual LARP by Branco Stefanovic, a professor in the FSU College of Medicine, who has spent much of his career researching fibrosis.

They tried several techniques to examine the protein, including X-ray crystallography, before finally finding success with NMR spectroscopy. "In NMR spectroscopy, we can look at the complex in solution close to its natural environment under physiological conditions," said Silvers. "NMR spectroscopy is ideal as we can study the dynamics of a molecule as well as its structure." NMR spectroscopy is a technique that uses the magnetic properties of certain nuclei to show the detailed structure and behavior of a molecule. It turned out to be especially helpful in this case because LARP6 is unstable on its own and becomes stable only when it binds to RNA. This protein is responsible for fibrosis. This insight could eventually help scientists develop new treatments for fibrosis.

Author: Anneswa Das, Editor: Arya Bandyopadhyay