Active Cells, Biochemistry & Physiology Genetics & Molecular Biology

Mechanisms of membrane protein quality control

Funder Wellcome Charity-funded
Recipient organisation University of Oxford
Funding £1.8M
Period Feb 2022 — Jan 2027

In plain English

AI plain-English summary

Every cell in the human body relies on a microscopic quality-control system to weed out faulty proteins lodged in its membranes, but scientists still do not understand how that system recognises its targets. The endoplasmic reticulum (ER) is the cell’s protein factory. When it produces a defective membrane protein, the ER-associated degradation (ERAD) pathway should flag it for destruction. Researchers already know how ERAD handles proteins floating freely inside the ER, but the mechanism for catching proteins embedded in the membrane itself remains unknown. This project aims to answer three fundamental questions: which ERAD branches handle which membrane proteins, how they recognise them, and how they drag them out of the membrane for disposal. This is fundamental science with no immediate clinical application. Defects in protein quality control are linked to developmental disorders and neurodegenerative diseases such as Parkinson’s, so understanding the basic machinery could eventually point toward new therapeutic targets. Past work on similar cellular cleanup pathways has already led to drugs that stabilise faulty proteins in cystic fibrosis, illustrating how mechanistic insights into fundamental biology can quietly reshape medicine decades later.

View original technical description
The endoplasmic reticulum (ER) is the largest membrane-bound organelle in cells, playing numerous essential functions including the biogenesis of secreted and membrane proteins, lipid synthesis and assembly of the nuclear envelope. A long-term goal of my lab is to dissect how these functions are coordinated and ER homeostasis achieved. Proteolysis through the ER-associated degradation (ERAD) pathway has emerged as key in maintaining ER homeostasis and this proposal aims at understanding its mechanistic basis, with a particular focus on membrane protein substrates. ERAD is organized in multiple branches, thereby targeting a broad range of luminal and membrane substrates. The mechanisms by which luminal substrates are selected and processed by the ERAD machinery are well established. In contrast, the mechanisms by which ERAD targets membrane substrates are mysterious and several fundamental questions remain: (1) what are the preferences of the various ERAD branches for membrane substrates? (2) what are the molecular basis for their recognition? (3) how are membrane substrates translocated to cytosol for degradation? Addressing these issues will reveal key mechanisms of membrane protein quality control by ERAD. Given that defects in protein quality control are linked to various pathologies, from developmental diseases to neurodegeneration, our studies may have clinical relevance.

View the original record at the funder ↗

Researchers

Pedro Carvalho (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

The mechanisms and physiology of ER-associated protein degradation
Structural studies on ER-associated protein quality control mechanisms
The use of newly discovered inhibitors to identify novel components of the ER associated degradation pathway.
Elucidating the contributions of ubiquitin ligase complexes to endoplasmic reticulum associated degradation (ERAD)
Translation-associated quality control of protein secretion.

Original classification

Investigator Award in Science

Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.