Wilmanns Group

Figure 1: DAPK-CaM complex. Colour codes: DAPK, green; CaM, red. (de Diego et al., 2010)

Wilmanns Group

Figure 2: AGT-(Pex5p)2-AGT complex. Colour codes: AGT, yellow, orange; Pex5p, cyan, magenta. (Fodor et al., 2012)

The Wilmanns group aims to unravel the overall architecture of protein translocation machineries across membranes by employing an integrative structural biology approach.

The architecture of the protein interactome in sarcomeric muscle cells: Many proteins found in muscle cells, when dysfunctional, are associated with cardiovascular diseases. We investigate how large protein filament systems forming the overall architecture of ‘sarcomeric units’ in muscle cells are connected and interact with each other, frequently mediated via small scaffold proteins. We have determined the structure and function of some key complexes, including telethonin-mediated assembly of the N-terminus of titin (Zou et al., 2006) and the overall architecture of the elastic filament protein myomesin (Pinotsis et al., 2008; 2012). Our future focus will be on novel protein interactions within the sarcomeric Z-disk and M-line region, and novel signalling functions of the protein partners involved.

Activity regulation in protein kinases

About 70 protein kinases in the human kinome share a common C-terminal autoregulatory domain. To investigate the mechanism of activity regulation in these kinases, we determined the structure of the kinase domain from the giant filament protein titin, in the inhibited apo-conformation (Mayans et al., 1998) and unravelled the structure of the apoptotic Death Associated Protein Kinase-1, in the presence of the regulatory scaffold calcium/calmodulin (CaM) (figure 1). This structure provides insight into how CaM binding leads to kinase activation by withdrawing the autoregulatory domain from the kinase active site. Ongoing structural studies are complemented by in vitro and in vivo functional studies, to decipher underlying, general molecular mechanisms that regulate the activity of members of the CaM-dependent protein kinase family and ultimately promote drug discovery.

The architecture of the translocon of peroxisomes

Peroxisomes are cell organelles that allow sequestered metabolic processes that would interfere with other processes in the cytosol. Proteins involved in these processes are generally translocated as active and folded targets. We have unravelled the mechanism involved in the recognition of peroxisome protein targets by the peroxisome import receptor Pex5p, by determining the structure of the cargo-binding domain of the receptor in the absence and presence of the cargo protein sterol carrier protein 2 (Stanley et al., 2006) and alanine-glyoxylate aminotransferase (figure 2). Our goal is to provide insight into the overall architecture of the peroxisomal translocon, using a broad range of structural biology, imaging, genetic and cell biology-oriented approaches.

Structural systems biology in M. tuberculosis

We have determined the X-ray structures of a number of protein targets. For instance, we were able to identity Rv2217 as a novel cysteine/lysine dyad acyltransferase, which allows activation of several important protein complexes by lipoylation (Ma et al., 2006). Using available structural data and supported by European research network systeMTb, we aim to use systems biologyorientated approaches to investigate functional processes in living mycobacteria, with the aim of making data available to promote the development of new drugs, vaccines and diagnostic markers.

Chemistry at EMBL