Defining mechanisms and function of protein UFMylation
Award Number
BB/T008172/1Status / Stage
ActiveDates
1 September 2020 -31 August 2023
Duration (calculated)
02 years 11 monthsFunder(s)
BBSRC (UKRI)Funding Amount
£657,310.00Funder/Grant study page
BBSRC UKRIContracted Centre
University of DundeePrincipal Investigator
Dr Yogesh KulathuPI Contact
y.kulathu@dundee.ac.ukPI ORCID
0000-0002-3274-1642WHO Catergories
Understanding Underlying DiseaseDisease Type
Dementia (Unspecified)CPEC Review Info
| Reference ID | 722 |
|---|---|
| Researcher | Reside Team |
| Published | 07/07/2023 |
Data
| Award Number | BB/T008172/1 |
|---|---|
| Status / Stage | Active |
| Start Date | 20200901 |
| End Date | 20230831 |
| Duration (calculated) | 02 years 11 months |
| Funder/Grant study page | BBSRC UKRI |
| Contracted Centre | University of Dundee |
| Funding Amount | £657,310.00 |
Abstract
Ubiquitin fold modifier 1 (UFM1) is a ubiquitin-like protein modifier (UBL) that plays essential roles in endoplasmic reticulum (ER) homeostasis and secretory and membrane protein expression. It is essential for tissue development and viability of many cell types. However, very little is known about how proteins are modified with UFM1, which proteins are modified, and how the process is regulated by UFM1 proteases. Further, human cells lacking the known UFM1 protease, UFSP2, still have deUFMylating activity, suggesting the presence of a hitherto unidentified UFM1 protease (UFSPx). The overall objectives of this proposal are to define how UFM1 is conjugated onto substrates and to identify and characterize the UFM1 proteases that remove the modification. Understanding how UFMylation regulates biogenesis of secretory and membrane proteins will advance our understanding of basic cell biology and reveal why failure in UFMylation results in ER stress and cell death. The specific aims of this project are 1) to characterize at the molecular level how UFL1 functions as an enzyme to catalyse the transfer of UFM1 onto substrates, even though it has no recognizable ligase domains; 2) to understand how specificity is provided by adaptors of UFL1 that direct UFMylation onto specific substrates; 3) to define the deUFMylating enzymes that regulate UFM1 processing and cellular functions of UFM1. The proposed project will use biochemical and structural approaches aided by recently developed chemical biology tools and novel methodologies to define how and when UFM1 is attached to distinct substrates by UFL1. Achieving the objectives of this proposal will reveal insights into mechanisms of protein UFMylation that will accelerate research into this essential but poorly understood PTM.
Aims
The overall objectives of this proposal are to define how UFM1 is conjugated onto substrates and to identify and characterize the UFM1 proteases that remove the modification.