Researchers from Weill Cornell Medicine – Qatar (WCM-Q) have discovered that a protein known to play a key role in cholesterol uptake and brain development is also crucial to the process of reproduction.

Dr Nancy Nader
Dr Nancy Nader

Discovered in 1922, the Very Low-Density Lipoprotein Receptor (VLDLR) protein, has long been known to facilitate the migration of neurons in the developing brain and to play a role in cholesterol uptake. Up until now its role as a ‘chaperone’ protein for membrane receptor trafficking was unknown.

Lead author Dr Nancy Nader, Research Associate in Physiology and Biophysics at WCM-Q explained that the role of the hormone progesterone in turning immature oocytes (ovarian cells) into mature eggs, in a process known as ‘oocyte maturation’ that prepares the cell for fertilisation, is well known.

Progesterone mediates its action by binding to a specific protein, known as the membrane progesterone receptor (mPR), located at the plasma membrane, which is the outer membrane of the cell. However, the early steps that trigger oocyte maturation at cellular level are still unknown. By studying frog oocytes in the laboratory, we were able to discover that the VLDLR protein acts as a ‘delivery truck’ or chaperone that helps deliver mPR to the plasma membrane and hence mediates its action after progesterone treatment.’

Untargeted Quantitative Proteomics

The WCM-Q team used a research approach known as untargeted quantitative proteomics to study the interactions of proteins at cellular level. Using this technique, they were able to identify VLDLR as an mPR-interacting protein. The research team also made use of advanced biochemistry and microscopy techniques to confirm the findings. Interestingly, by knocking down VLDLR protein levels within oocytes, they observed an inhibition of oocyte maturation and significantly much less mPR at the plasma membrane.

Explaining in more detail, Dr Nader said that the VLDLR protein associates intracellularly with the mPR protein and assures its transport from a part of the cell called the Golgi body, which serves as a delivery depot, to the plasma membrane.

In basic terms, we need mPR to be delivered to the right place which is the plasma membrane, to allow progesterone-mediated oocyte maturation to produce mature eggs that can be fertilised for a new life to begin. Our study has shed light on how one of the previously unknown journeys of a protein within the cell actually takes place, giving us a clearer understanding of cellular function in general and of reproduction.’

The study, entitled The VLDL receptor regulates membrane progesterone receptor trafficking and non-genomic signaling, has now been published in a leading international journal, the Journal of Cell Science. The research was considered so significant that the journal  recognised Dr Nader’s contribution in their ‘First Person’ series of articles.

The study was supported by the Qatar National Research Fund and the Biomedical Research Programme of WCM-Q, a programme supported by Qatar Foundation.

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Image Cover: A cartoon representation of the molecular structure of protein registered with 1v9u code (Source: Wikipedia)