Mechanisms of Protein Involved in Cardiovascular Disease and Cancer Uncovered
A new study has shown for the first time how the protein PCSK9 breaks down cholesterol receptors, a key step towards uncovering the mechanisms underpinning cardiovascular disease as well as certain cancers. The study is published in Molecular Metabolism.
Cholesterol and PCSK9
Low-density lipoproteins, or LDL, can lead to the buildup of cholesterol in arteries which can in turn lead to atherosclerosis – a hardening and narrowing of the arteries – as well as heart disease.
LDL receptors (LDLR) bind to LDL molecules and their associated cholesterol (LDLc), collecting and internalizing them, mainly into liver cells. The internalized LDL is captured within the cell, and the LDLR is then transported back to the cell surface to collect more LDL molecules.
Dysfunctions in the LDLR can lead to familial hypercholesterolemia, a condition that causes exceptionally high levels of LDL in the blood. However, some rare cases of familial hypercholesterolemia have also been linked to a protein called proprotein convertase subtilisin/kexin type 9 (PCSK9).
PCSK9 was discovered in 2003 in the lab of Nabil G. Seidah, medical professor at the University of Montreal. PCSK9 is found in the bloodstream where it binds to the LDLR – however, instead of allowing LDLR to cycle back to the cell surface after it is internalized, LDLR is degraded, preventing it from returning to the surface of the cell to collect LDL.
Treatments have been developed recently that either impair the function of PCSK9 or reduce its levels in the blood, thereby limiting the degradation of LDLR. This can result in a drop in LDLc of over 60% when compared to other cholesterol-lowering drugs such as statins.
In the current study, Seidah and colleagues further investigated the functions of PCSK9, uncovering the mechanism by which PCSK9 degrades LDLR.
PCSK9 as a potential drug target
The researchers analyzed the structure of PCSK9, revealing how it forms a complex alongside three other proteins: LDLR, cyclase-associated protein 1 (CAP1) and human leukocyte antigen C (HLA-C).
HLA-C is found on the outside of cells and acts as part of the immune system, helping the recognition of “self” from “non-self” cells and stimulating tumor-fighting T lymphocytes. It also has a key role in directing the PCSK9 protein complex to the lysosomes within the cell – membrane-bound organelles containing digestive enzymes – for its destruction. Additionally, PCSK9 can aid HLA-C’s tumor-fighting abilities by increasing the number of HLA-C molecules on the cell surface.
The researchers hope that the information gathered on the function of PCSK9 from this breakthrough study may lead to the development of inhibitors that can block the negative interactions with LDLR and HLA-C, which could potentially be used to help treat cardiovascular disease and cancer.
Reference: Fruchart Gaillard C, Ouadda ABD, Ciccone L, et al. Molecular interactions of PCSK9 with an inhibitory nanobody, CAP1 and HLA-C: Functional regulation of LDLR levels. Mol. Metab. 2023;67:101662. doi: 10.1016/j.molmet.2022.101662