Cholesterol homeostasis in mammals is tightly controlled by its biosynthesis, dietary intake and cellular uptake from the blood. The low-density lipoprotein receptor (LDLR) is responsible for the cellular uptake of cholesterol in the form of low-density lipoprotein cholesterol (LDL-C). At the surface of hepatocytes and other cells, LDLR binds LDL-C and the complex is then internalized by receptor-mediated endocytosis. The activity of LDLR is tightly regulated through its biosynthesis, surface localisation, internalisation, recycling and degradation, in order to maintain cellular cholesterol homeostasis. Recently we have identified that LDLR is proteolytically cleaved at a physiologically-relevant site within its ligand-binding domain by the zinc metalloprotease bone morphogenetic protein 1 (BMP1) (Banerjee et al. 2019). The cleavage of LDLR by BMP1 reduces the binding and endocytosis of LDL-C. Thus proteolytic cleavage of LDLR by BMP1 is a new mechanism to regulate cellular LDL-C uptake. We hypothesise that molecular interactions between BMP1, LDLR and other cellular components regulate the proteolytic cleavage of LDLR by BMP1 and impact on LDL-C metabolism. To address this hypothesis, the objectives of this proposal are to: 1) determine the role of the non-catalytic protein-protein interaction domains on BMP1 in the recognition and cleavage of LDLR; and 2) identify the proteins that bind BMP1 or LDLR to regulate the proteolytic cleavage of LDLR by BMP1 and hence LDL-C endocytosis.This work will contribute to our understanding of the biological mechanisms controlling the cellular uptake of LDL-C and could lead to new molecular targets to modulate LDLR action and manage cholesterol homeostasis.
https://www.research.manchester.ac.uk/portal/en/researchers/nigel-hooper(1a3e734e-f35c-43e1-a802-6cd42e6befa9).html
https://www.research.manchester.ac.uk/portal/en/researchers/clair-baldock(76a9ca58-a57f-475b-82f5-2d7ef2202e87).html
https://www.wellcome-matrix.org/people/clair-baldock/
Entry Requirement
Applicants must have obtained or be about to obtain a First or Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in an appropriate area of science, engineering or technology.
Applicants interested in this project should make direct contact with the Primary Supervisor to arrange to discuss the project further as soon as possible.
How To Apply
To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the BBSRC DTP website www.manchester.ac.uk/bbsrcdtpstudentships
Equality, Diversity and Inclusion
Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/
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