Determining the structure and function of protein S-acyltransferases that modify signal transducing proteins

Lead Research Organisation: Imperial College London
Department Name: Life Sciences

Abstract

Many proteins become attached to cell membranes and targeted to their proper destinations inside cells by having fatty molecules attached to them – we are trying to understand this process called S-acylation. These proteins are commonly involved in regulating cell growth and function and their inappropriate activation can cause disease such as cancer. Studies in yeast have recently provided clues to the identity of the enzymes that attach these fatty molecules to the proteins. We will identify the human enzymes that carry out this process and use molecular and cellular techniques to study their function. Ultimately, by understanding and interfering with these enzymes it may be possible to treat diseases that are caused by inappropriate activity of their target proteins.

Technical Summary

Protein:S-acylation is a key post-translational hydrophobic modification of proteins that targets them intracellularly to specific membrane sites where they carry out their functions. Protein:S-acyltransferase (PAT) enzymes have recently been identified in yeast and 23 human homologues (DHHC-CRD genes) have been identified by database searching. We propose to determine which of these proteins carries out S-acylation of the signalling molecules N-/H-Ras and Lck which have different S-acylation sites. We will then study the functional consequences of knocking down S-acylation of these proteins. We will also study the structure and function of one of the PATs.

Publications

10 25 50
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Chang SC (2009) Acyltransferases for secreted signalling proteins (Review). in Molecular membrane biology

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Konitsiotis AD (2015) Topological analysis of Hedgehog acyltransferase, a multipalmitoylated transmembrane protein. in The Journal of biological chemistry

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Masumoto N (2015) Membrane bound O-acyltransferases and their inhibitors. in Biochemical Society transactions

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Zeidman R (2009) Analysis of protein acylation. in Current protocols in protein science

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Zeidman R (2009) Protein acyl thioesterases (Review). in Molecular membrane biology

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Zeidman R (2011) DHHC2 is a protein S-acyltransferase for Lck. in Molecular membrane biology

 
Description CRUK Discovery Committee Award
Amount £200,000 (GBP)
Funding ID C6433/A16402 
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2013 
End 05/2015
 
Description MRC Confidence in Concept Scheme and Wellcome Trust Institutional Strategic Support Fund
Amount £57,920 (GBP)
Funding ID PS3085_CHBBT and PS3110_CHBBC 
Organisation Medical Research Council (MRC) 
Department MRC Confidence in Concept Scheme
Sector Charity/Non Profit
Country United Kingdom
Start 10/2017 
End 10/2018
 
Description Pancreatic Cancer Research Fund project grant
Amount £189,000 (GBP)
Organisation Pancreatic Cancer Research Fund 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2011 
End 01/2014