Membrane proteins are biologically and medically relevant. In fact, some genetic human diseases are caused by their misassembly e.g. cystic fibrosis, a lethal hereditary disorder. CF is caused by mutations in the gene encoding the cystic fibrosis transmembrane regulator (CFTR). This is a chloride-conducting transmembrane channel. Recently, structures of human CFTR in complex with small molecule drugs were reported. Here, I will discuss these structures and our current understanding of CFTR.
Mitochondrial proteases are crucial for maintaining mitochondrial activity. These include ClpP, which in humans, is a key factor in different tumors, thereby contributing to the role of mitochondria as mediators of oncogenesis. Potent anticancer drugs have been developed that exert activity through hyperactivating ClpP. Recently, detailed structures of human ClpP in complex with these hyperactivators were reported. Here, I will discuss these structures as well as how these hyperactivators work.
The ability to rapidly export drugs from the cell represents a powerful mechanism of bacteria to achieve high-level multidrug resistance. P aeruginosa contains numerous efflux pumps, explaining its exceptionally high dug resistance. Of these, the MexAB-OprM system represents the best characterized multidrug efflux pump. Recently, novel structures of the MexAB-OprM pump were presented. Here I will discuss these structures as well as its functional understanding.
Gram-negative bacteria are insensitive to antibiotics effective against Gram-positives. This is because their cell wall contains a protective LPS layer that is produced in the cytoplasm and transported to the cell surface. This depends on Lpt proteins that form a bridge spaning the cell envelope. Recently structures of the Lpt complex responsible for LPS extraction and transfer to the Lpt bridge were reported. Here, I will discuss these structures as well as the understanding of LPS transport.
Cholesterol is linked with cardiovascular diseases and should not be viewed as bad because life would not be possible without it. The biosynthesis of cholesterol requires different enzymes e.g. SQLE. This is a flavin-dependent monooxygenase that is pharmaceutical relevant. Recently, structures of human SQLE have been reported contributing to the design of novel drugs. Here, I will discuss these structures as well as our current mechanistic understanding of this enzyme.
Mitochondria are essential eukaryotic organelles. Their proper activity is crucial for health. The mitochondrial inner membrane houses important protein complexes. Maintaining the quality of the IM proteome is key for safeguarding mitochondrial funtioning. Two proteases, i-AAA and m-AAA, play an important role in this process. Recent structures of these proteases offered profound insight into their functioning. Here, I will discuss these structures and how these enzymes handle substrate proteins
The Sec complex is key for protein export. In eukaryotes, Sec61 facilitates protein transport across the ER membrane. This can occur post or co-translationally and requires a different Sec61 system. In yeast, post-translational export is performed by the Sec61 pore and the Sec62/Sec63 complex. Recent structures of the post-translational Sec complex have provided crucial insight into this. Here, I will discuss these novel structures and our understanding of post-translational translocation.
In eukaryotes, most proteins are degraded by the ubiquitin-proteasome pathway. The proteasome is a large proteolytic complex that comprises a barrel-shaped 20S hydrolytic core particle and one or two copies of the 19S regulatory particle. The proteasome plays a key role in modulating the eukaryotic proteome and its malfunctioning is associated in humans with cancer, Alzheimer’s and ALS. Here, I will discuss novel proteasome structures as well as the current understanding of proteasome function.
Secreted and integral membrane proteins account for one-third of a typical biological proteome. To reach their target destination, these proteins have to traverse at least one biological membrane which is typically facilitated by the universally conserved Sec translocon. Recent structures of the translocon in different functional states revealed its molecular mechanism in unprecedented detail. Here, I will discuss the current understanding of Sec-dependent translocation.
Gram-negative bacteria are decorated with LPS that is essential for cell viability. LPS performs a crucial barrier function and protects the cell against harsh environments. Seven essential proteins – LptABCDEFG - are required to transport LPS from the periplasmic face of the inner membrane to the OM. At the OM, LPS is inserted by a two-protein complex, LptDE. Here, I will discuss the biochemical and structural properties of LptD and E.