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Mechanisms controlling organelle dynamics and quality control


Sir William Dunn School of Pathology

Prof P Carvalho Friday, January 08, 2021 Competition Funded PhD Project (Students Worldwide)

About the Project

Our lab is interested in membrane-bound organelles- how they form and acquire their distinctive proteome essential to carry their specialized functions. In particular, we focus on how organelle function is maintained through quality control processes. Our lab has been particular interested in a quality control process termed ERAD, which targets misfolded membrane proteins in the endoplasmic reticulum (ER). While some of the components of this process have been identified, the mechanisms by which diverse range of misfolded proteins are selected, ubiquitinated, extracted from the ER membrane and targeted for degradation by the proteasome remain elusive. To gain insight on the mechanisms of protein quality control our lab is taking multidisciplinary approaches. We are using CRISPR-based genome-wide genetic screens to delineate the molecular pathways involved in the degradation of disease-relevant misfolded proteins. In parallel, we use biochemical, proteomics and structural approaches to dissect mechanistically the multiple steps of ERAD. These studies will reveal the molecular basis of quality control processes by which misfolded and aggregation-prone proteins are handled by the cell both under normal and pathological situations. We are also interested in inter-organelle communications- which and how molecules are exchanged between organelles, which signals regulate those exchanges, etc. Although we do mostly basic research, we are interested how these processes are disrupted in human disease.

Funding Notes

4 Year DPhil Prize Studentships cover University fees, a tax free stipend of ~£17,009 pa, and up to £5,300 pa for research costs and travel. The competition is open to applicants from all countries. See View Website for full details and to apply.

References

van de Weijer M, Krshnan L, Liberatori S, Guerrero EN, Robson-Tull J, Hahn L, Lebbink RJ, Wiertz E, Fischer R, Ebner D, Carvalho P (2020). Quality Control of ER Membrane Proteins by the RNF185/Membralin Ubiquitin Ligase Complex. Mol Cell. Jul 24; S1097-2765(20)30475-5.
Natarajan N, Foresti O, Wendrich K, Stein A, Carvalho P. (2020) Quality Control of Protein Complex Assembly by a Transmembrane Recognition Factor. Mol Cell. Jan 2;77(1):108-119
Olzmann JA, Carvalho P. (2018) Dynamics and functions of lipid droplets. Nat Rev Mol Cell Bio doi: 10.1038/s41580-018-0085-z
Wu H, Carvalho P, Voeltz GK (2018) Here, there, and everywhere: The importance of ER membrane contact sites. Science 361(6401)
Wang S, Idrissi FZ, Hermansson M, Grippa A, Ejsing CS, Carvalho P (2018). Seipin and the membrane-shaping protein Pex30 cooperate in organelle budding from the endoplasmic reticulum. Nat Commun.Jul 27;9(1):2939.
Foresti O, Rodriguez-Vaello V, Funaya C, Carvalho P. (2014) Quality control of inner nuclear membrane proteins by the Asi complex. Science. 346(6210):751-5.

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