The Most Common Mutation of Retinitis Pigmentosa - How Does It Impact Rhodopsin?

How does the P23H mutation impact protein structure and function?

The P23H mutation (GIF 2) is located outside of the membrane, facing the outer segment of the rod and results in misfolding of rhodopsin.(1) The outer portion of rhodopsin is important for maintaining the helical region of the protein.(2) P23H has less helical structure and less interactions in the 3-dimensional structure, which means that it is less compacted than normal rhodopsin.(2,3) The dysfunctional protein P23H can result in 2 different forms:

1. P23H cannot bind retinal and therefore cannot be activated.(3)

2. P23H can partially bind retinal.(3)

Without proper functioning of retinal, P23H rhodopsin activation is minimised which hinders the pathway leading to vision.(12) Normal rhodopsin is trafficked from the inner segment of the rod cell to the outer segment via structures in the cell including the endoplasmic reticulum.(2) P23H rhodopsin doesn’t undergo proper trafficking, leading to its build-up within the endoplasmic reticulum.(4)

Observe the location of normal P23 (GIF 1) vs. P23H (GIF 2) below.

References

1. Palczewki K, Kumasaka T, Yamamoto M, Miyano M, Hori T, Behnke CA, Motoshima H, Fox BA, Le Trong I, Teller DC, Okada T, Stenkamp RE. Crystal Structure of Rhodopsin: A G Protein-Coupled Receptor. Science (AAAS) [Internet]. 2000 [cited 2022 Sept 30];289(5480):739-745. Available from: https://go.gale.com/ps/i.do?p=AONE&u=monash&id=GALE%7CA64697932&v=2.1&it=r

2. Kosmaoglou M, Kanuga N, Aguila M, Garriga P, Cheetham ME. Dual role for EDEM1 in the processing of rod opsin. J. Cell Sci.[Internet]. 2009 [cited 2022 Oct 10];122(24):4465-4472. Available from: https://pubmed.ncbi.nlm.nih.gov/19934218/

3. Liu X, Garriga P, Khorana HG. Structure and Function in Rhodopsin: Correct Folding and Misfolding in Two Point Mutants in the Intradiscal Domain of Rhodopsin Identified in Retinitis Pigmentosa. Proc. Natl. Acad. Sci. [Internet]. 1996 [cited 2022 Oct 10];93(10):4554-4559. Available from: https://www.jstor.org/stable/38812?saml_data=eyJzYW1sVG9rZW4iOiI4MWM3YjM2Zi00ZTc5LTRiMTctOThjMi00Zjk5NmU0MGJhN2UiLCJpbnN0aXR1dGlvbklkcyI6WyIxMDk1NWQ2YS1kMjQ2LTQyODMtYWNlNS03ZTVhMGI3ODkwZTgiXX0#metadata_info_tab_contents

4. OMIM [Internet]. Baltimore, MA: John Hopkins University; 1996. RETINITIS PIGMENTOSA 4; RP4; March 24 2021 [cited 2022 Sept 30]; [about 20 screens]. Available from: https://www.omim.org/entry/613731?search=Retinitis%20pigmentosa&highlight=pigmentosa%20retiniti

5. Schrödinger L, DeLano W. PyMOL [Internet]. 2020. Available from: http://www.pymol.org/pymo