"Insight into the 3D structures of proteins is key to understanding the molecular mechanisms that underlie biological processes."
Piet Gros (Dokkum, 1962) is a protein chemist and structural biologist. He and his research team at Utrecht University focus on elucidating the molecular mechanisms that underlie biological processes with a major emphasis on human plasma-proteins and cell-surface receptors and (human and bacterial) membrane proteins.
Research themes and highlights
A major focus has been on interactions of plasma proteins and cell-surface receptors in biomedical important processes. Highlights include:
- the elucidation of the key steps in the humoral immune response through the complement system. The ground-breaking structure of C3 (Janssen et al. Nature 2005), C3b (Janssen et al. Nature 2006), factor B (Milder et al. Nature SMB 2007), C3 convertase (Rooijakkers, Wu et al. Nature Immun. 2009) and its formation through C3bB by factor D (Forneris et al. Science 2010), altogether revealed the mechanisms underlying amplification and opsonisation by the central ‘alternative’ pathway of complement activation. Structures of C3b in complex with regulators (Wu et al. Nature Immun. 2009, Forneris et al. EMBO J 2016) together with the ternary complex including factor I (Xue et al. Nature SMB 2017) revealed mechanisms underlying host cell protection. Elucidation of C1 complement activation by IgG and IgM antibodies had marked impact on both mechanistic understanding of initiation of the proteolytic cascade and has potent therapeutic application (Diebolder et al. Science 2014, Ugurlar et al. Science 2018, Sharp et al. PNAS 2019). With respect to the terminal pathway of complement that leads to cell lysis, C8a-MACPF (Hadders et al. Science 2008) revealed mechanistic homology to bacterial cholesterol-dependent beta-barrel pore forming cytolysins, C5b6 (Hadders et al. Cell Reports 2012) with cryo-ET imaging (Sharp et al. Cell Reports 2016, Sharp et al. J. Structural Biology 2017) provided insights into cell lysis by MAC formation. Most recently, we developed a toolbox of nanobodies against C4b to interfere with the classicla pathway of complement activation (de la O Becerrra et al. Journal of Immunology 2022). For reviews see e.g. Gros et al. Nature Reviews Immunology 2008 and Geisbrecht et al. Seminars in Immunology 2022;
- insights into regulation of Wnt signaling by R-spondins (Peng et al. Cell Reports 2013, de Lau et al. Genes and Development 2014), von Willlebrand factor interacting with platelet receptor GpIbalpha in the arrest of bleeding (Huizinga et al. Science 2002), beta2-Glycoprotein I involved in anti-phospholipid syndrome (Bouma et al. EMBO J 1999);
- outer-membrane proteins contributing to infections by pathogenic bacteria, including ‘omptin’ OmpT (Vandeputte-Rutten et al. EMBO J 2001), NspA (Rutten et al. JBC 2003) autotransporter NalP (Oomen et al. EMBO J 2004). PagL (Rutten et al. PNAS 2006) and LpxR (Rutten et al. PNAS 2009);
In addition, we have contributed to structure-determination and analysis methodology:
- modelling protein dynamics by (time-averaged) ensemble refinement of crystallographic data (Gros et al. Science 1990, Burnley et al. eLife 2012)
- extracting macromolecular dynamics from strutural disorder by refactoring the B factor (Pearce and Gros, Nature Comm 2021) and its use in ensembl refinement (Ploscariu et al. Acta Cryst D 2021).
The obtained fundamental insights underpin diverse research programs, both in academia and pharmaceutical industry, for the development of novel therapeutic approaches.
Piet Gros is extremely grateful for the many excellent contributions of the PhD students, post-doctoral fellows and technicians in his lab.
For more information see: Piet Gros' lab