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.
Antibiotics are powerful drugs used to treat bacterial infections. The antibiotic resistance crisis represents a global health threat because bacterial infections become difficult or impossible to treat. Different antibiotic resistance mechanisms are known. Nevertheless, knowledge about emerging resistance mechanisms, such as enzymatic inactivation, is crucial. Here I will discuss the molecular features of rifamycin monooxygenase, an enzyme that detoxifies the frontline antibiotic rifampicin.
Bacterial lipoproteins are membrane proteins involved in e.g. signal transduction and transport. Moreover, they contribute to virulence and antibiotic resistance. Lipoproteins are synthesized as precursors and are after export subjected to posttranslational steps that are catalyzed by specific enzymes. These are not present in eukaryotes and are therefore of interest as potential drug target. Here, I will discuss the structural features of the bacterial lipoprotein maturation enzymes.
Tetracycline antibiotics are crucial in human and animal health due to their broad activity against bacteria, including drug resistant ones. Resistance to tetracyclines is based on efflux and ribosomal protection, while new mechanisms include degradation by tetracycline destructases. These are flavin-containing monooxygenases that catalyze the oxidation of tetracyclines, resulting in their degradation. Here, I will discuss the molecular features of these tetracycline resistance enzymes.
Many diseases are caused by aggregation of proteins e.g. Alzheimer’s and Huntington’s. Normally, protein folding is monitored in the cell by a quality control system containing chaperones and proteases. These ensure the proper folding of proteins and removal of dysfunctional ones. Additionally, cells possess chaperones that are able to refold aggregated proteins. Yeast Hsp104 and bacterial ClpB are well known examples. Here, I will discuss structural and biochemical properties of ClpB/Hsp104,