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Research in the Müller lab focuses on developing and applying chemical biology tools elucidate how proteins are controlled by molecular on/off switches, so-called post-translational modifications. We are particularly interested in modifications of the polypeptide backbone, and how these and more traditional modifications are involved in cellular life and death decisions. To answer these questions, we use semi-synthesis to generate ‘designer’ proteins – including the tumour suppressor p53, viral anticancer proteins and histones – allowing us to directly measure the structural and functional consequences of modifications. In parallel, we develop novel strategies to discover backbone modifications and their roles in molecular ageing and signalling. Manuel is a Wellcome Trust/Royal Society Sir Henry Dale Fellow.

People

PhD Student

PhD Student

PhD Student

Luis F. Guerra

Postdoctoral Research Associate

Mateusz  Hess

PhD Student

Themes

Molecular diagram of protein backbones
Post-translational modifications of protein backbones

The polypeptide backbone makes up approximately 50% of every protein's mass. Originally thought to be inert, emerging evidence suggests that protein backbones are subject to a plethora of site-specific post-translational modifications. Similarly to well-studied modifications of amino acid side chains, backbone modifications can control protein structure and function. We are developing and applying a suite of chemical biology technologies to reveal when, where and how backbone modifications impact biological processes.

    Diagram showing molecular ageing between molecules
    Molecular ageing

    Proteins are subject to spontaneous modifications, contributing to senescence phenotypes across all kingdoms of life. For example, asparagine and aspartate residues can rearrange to isoaspartate, and long-lived proteins including eye lens crystalline contain significant amounts of isoaspartate. We aim to elucidate the biochemical, biophysical and cellular mechanisms of isoaspartate formation and explore the exciting possibility that this post-translational modification is harnessed as a molecular timer in biology.

      Diagram showing process for a site-specifically modified protein
      Protein semi-synthesis

      We employ cutting edge protein semi-synthesis methods to prepare site-specifically modified proteins: chemical peptide synthesis enables the incorporation of diverse modifications and chemoselective ligation strategies permit the precise attachment of synthetic fragments to large recombinant proteins. Full-length proteins generated in this way enable us to directly measure how post-translational modifications control functional properties in biochemical, biophysical and cellular assays.

        Publications

          Awards

          2021                     Chemistry Biology Interface Division early career award: Norman Heatley                               Award, Royal Society of Chemistry 

          2016-2021            Sir Henry Dale Fellowship, Wellcome Trust and the Royal Society

          People

          PhD Student

          PhD Student

          PhD Student

          Luis F. Guerra

          Postdoctoral Research Associate

          Mateusz  Hess

          PhD Student

          Themes

          Molecular diagram of protein backbones
          Post-translational modifications of protein backbones

          The polypeptide backbone makes up approximately 50% of every protein's mass. Originally thought to be inert, emerging evidence suggests that protein backbones are subject to a plethora of site-specific post-translational modifications. Similarly to well-studied modifications of amino acid side chains, backbone modifications can control protein structure and function. We are developing and applying a suite of chemical biology technologies to reveal when, where and how backbone modifications impact biological processes.

            Diagram showing molecular ageing between molecules
            Molecular ageing

            Proteins are subject to spontaneous modifications, contributing to senescence phenotypes across all kingdoms of life. For example, asparagine and aspartate residues can rearrange to isoaspartate, and long-lived proteins including eye lens crystalline contain significant amounts of isoaspartate. We aim to elucidate the biochemical, biophysical and cellular mechanisms of isoaspartate formation and explore the exciting possibility that this post-translational modification is harnessed as a molecular timer in biology.

              Diagram showing process for a site-specifically modified protein
              Protein semi-synthesis

              We employ cutting edge protein semi-synthesis methods to prepare site-specifically modified proteins: chemical peptide synthesis enables the incorporation of diverse modifications and chemoselective ligation strategies permit the precise attachment of synthetic fragments to large recombinant proteins. Full-length proteins generated in this way enable us to directly measure how post-translational modifications control functional properties in biochemical, biophysical and cellular assays.

                Publications

                  Awards

                  2021                     Chemistry Biology Interface Division early career award: Norman Heatley                               Award, Royal Society of Chemistry 

                  2016-2021            Sir Henry Dale Fellowship, Wellcome Trust and the Royal Society

                  Group lead

                  Contact us

                  Britannia House

                  7 Trinity Street – 112A

                  London

                  SE1 1DB