Matthias Mann on the First Quantitative & Proteome-Wide Study of Lysine Acetylation
New Hot Paper Commentary, November 2010
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Article: Article Title: Lysine Acetylation Targets Protein Complexes and Co-Regulates Major Cellular Functions
Authors: Choudhary, C;Kumar, C;Gnad, F;Nielsen, ML;Rehman,
M;Walther, TC;Olsen, JV;Mann, M |
Matthias Mann talks with ScienceWatch.com and answers a few questions about this month's New Hot Papers paper in the field of Molecular Biology & Genetics.
Why do you think your paper is highly
cited?
The paper describes the first quantitative and proteome-wide study of lysine acetylation, an important post-translational modification. Lysine acetylation had been studied mainly on specific proteins such as histones, p53, or tubulin. While it was always clear that lysine acetylation would not be restricted to just these protein classes, it was not appreciated just how widespread this modification is. In fact, our study revealed more than 3,600 specific lysine acetylation sites on 1,750 proteins in three human cell lines.
Does it describe a new discovery, methodology, or
synthesis of knowledge?
The paper applies a relatively novel methodology—high-resolution mass spectrometry using a quantitative proteomics method called SILAC—to the study of lysine acetylation. While lysine acetylation had been studied by mass spectrometry before, this had not been done in a quantitative way or with high-resolution methods. This approach then resulted in the discovery of an unexpected diversity of cellular regulation that is due to the enzymatic modification of lysines by acetylation.
Would you summarize the significance of your paper
in layman's terms?
PHOTO 1:
Close-up of an electrospray ionization source used to
analyze peptides in proteomics experiments
View larger image in tab below.
The paper revealed the nature and extent of a relatively little studied "cellular control system," namely the modification of thousands of proteins by lysine acetylation. Apart from its importance in understanding how the cell regulates its processes, it also has clinical implications because inhibitors of this control system (so called histone deacetylase or HDAC inhibitors) are under development for application in cancer and are, in fact, already in the clinic.
Aging is another important research field in which lysine acetylation is intimately involved. So a better understanding of this protein modification is likely to help our understanding of the clinical mechanisms of these drugs and the development of new ones.
How did you become involved in this research, and
how would you describe the particular challenges, setbacks, and
successes that you've encountered along the way?
Our group has been developing mass spectrometric and proteomics tools for many years. We have also studied post-translational modifications of proteins at a large scale for several years. So the extension to lysine acetylation was logical.
Also, HDAC inhibitors were approved by the Federal Drug Administration (FDA) for clinical use in 2006, just before Chuna Choudhary, the first author of the paper, joined my group. However, molecular targets of these drugs in cells remained largely unknown. Therefore, we wanted to develop a generic, sensitive, and robust method for identifying cellular acetylation sites, and their quantification in response to perturbations such as after treatment with HDAC inhibitors.
A challenge was that the tools to enrich peptides that bear the lysine acetylation are relatively poor. This means that one has to work with peptide populations that are not highly enriched for the modification.
Where do you see your research leading in the
future?
There is a lot of interest by many groups in basic research and in medically oriented research. The tools we applied here are currently being used to unravel the effects of knocking out specific elements of the lysine acetylation machinery. The involvement of lysine acetylation in specific biological processes—for example, DNA repair—is also being investigated. Researchers are also using our data set to directly probe for the function of the acetylation sites in proteins of their interest.
Do you foresee any social or political
implications for your research?
Not directly. Perhaps by contributing to the understanding of the lysine
acetylation system, our research can make a small contribution to cancer
and aging research, which would obviously have societal
implications.
Prof. Dr. Matthias Mann
Dept. Proteomics and Signal Transduction
Max-Planck Institute for Biochemistry
Martinsried, Germany
KEYWORDS: HISTONE DEACETYLASE INHIBITORS; MASS-SPECTROMETRY; POSTTRANSLATIONAL MODIFICATIONS; PROTEOMICS; ACTIVATION; SITE; ACETYLTRANSFERASE; PHOSPHORYLATION; QUANTIFICATION; RESOURCE.
