Final Report Summary - NEDD8ANDCRLLIGASES (Regulation and Function of Cullin-Ring E3 ubiquitin ligases and the Nedd8 ubiquitin-like protein modification system)
Cullin-RING Ligases (CRLs) are enzymes that regulate many aspects of biology. Because of their involvement in most cellular processes, they are also implicated in many human diseases. This project was aimed at elucidating the regulation and function of Cullin-RING ligases and to understand their role in disease.
CRLs are protein complexes that facilitate the degradation of other proteins by tagging them with a polypeptide called ubiquitin. In order to prevent erroneous protein degradation, CRLs need to be tightly regulated. We discovered how a class of proteins, called DCNs, leads to the activation of CRLs. We furthermore uncovered how another protein, CAND1, is required to make sure that CRL complexes are made up of the right consituents, by switching out different subunits.
Once we understood how CRLs are build and activated, we then studied a specific CRL that is important for the regulation of blood pressure. If this CRL, which is called CUL3-KLHL3, is not functioning properly, humans develop severe hypertension. We found out why that occurs, by showing that CUL3-KLHL3 is needed to degrade regulators of salt retention in the kidney. If CUL3-KLHL3 is not functioning properly, then too much salt is retained in the body, leading to severe hypertension.
CRLs are protein complexes that facilitate the degradation of other proteins by tagging them with a polypeptide called ubiquitin. In order to prevent erroneous protein degradation, CRLs need to be tightly regulated. We discovered how a class of proteins, called DCNs, leads to the activation of CRLs. We furthermore uncovered how another protein, CAND1, is required to make sure that CRL complexes are made up of the right consituents, by switching out different subunits.
Once we understood how CRLs are build and activated, we then studied a specific CRL that is important for the regulation of blood pressure. If this CRL, which is called CUL3-KLHL3, is not functioning properly, humans develop severe hypertension. We found out why that occurs, by showing that CUL3-KLHL3 is needed to degrade regulators of salt retention in the kidney. If CUL3-KLHL3 is not functioning properly, then too much salt is retained in the body, leading to severe hypertension.