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Ruiz-Rivera, A.

Publications and source records attributed to Ruiz-Rivera, A..

2 recordsLinked to original sources

Expression of soluble Type IV Minor Pilins and isolation of a Neisseria gonorrhoeae PilI-PilJ subcomplex

Type IV pili and type II secretion systems assemble dynamic fibers used by bacteria and archaea for diverse functions. The pilus fiber is made up of major and minor pilin subunits containing a hydrophobic -helical spine and a globular head. Purifying minor pilins is complicated by the hydrophobic -helical spine, frequently present disulfide bonds, and low abundance within the fiber. These challenges have impeded structural and functional studies of pilin protomers. Here, we describe a method for expression and purification of soluble type IV pilin proteins from Escherichia coli. Signal peptidase I cleavage sites are engineered into the -helix of the pilin proteins. This allows their globular domains to be purified from the periplasmic fraction. We used this method to obtain the Neisseria gonorrhoeae minor pilins PilI and PilK in soluble form. In a third case, where the minor pilin PilJ could not be obtained on its own, coexpression with PilI and purification of a PilI-PilJ heterodimer was possible. We suggest that PilI and PilJ form an obligate heterodimer that is essential for their function. ImportanceType IV pili are essential to many bacteria responsible for disease. They can be found in both Gram-negative and Gram-positive bacteria, as well as archaea, making them likely present in the last common ancestor of all life on Earth. Despite their significance in a variety of species, there are large gaps in our understanding of the structure of these diverse biological machines. One roadblock to this research has been the difficulty of purifying the minor pilin proteins that serve different functions in the fiber. Here, we describe a novel method for the purification of these proteins and demonstrate the ability of this method to identify a protein-protein interaction between two minor pilins of Nesseria gonorrhoeae.

microbiology↗

Structural and functional analysis of cancer-associated missense variants in the retinoblastoma protein (Rb) pocket domain

The retinoblastoma tumor suppressor (Rb) is a multifunctional protein that primarily regulates the cell cycle but also has roles in cellular differentiation, DNA damage response and apoptosis. The loss of Rb is a key event in the development or progression of many cancers. Essential functions of Rb occur through its pocket domain, which is necessary for regulating binding interactions with E2F transcription factors and transcription repressors that bind via an LxCxE motif. The pocket domain is the most highly-conserved region of the multidomain protein, as well as the most frequent site of mutations. To understand what effects cancer missense mutations have on Rbs pocket domain, we used fluorescence polarization and differential scanning fluorimetry to quantify changes, caused by 75 cancer-associated missense variants, to E2F transactivation domain (E2FTD) binding, LxCxE binding, and changes to the thermostability of the protein. We find that 43% of the missense variants we tested reduce Rb-E2FTD binding. Many of these variants are not located at the E2F binding site, yet they destabilize the fold of the protein and show temperature-sensitive binding effects. We also find that 21% of tested mutations reduce LxCxE binding, and several mutations selectively disrupt either E2FTD or LxCxE binding. Protein X-ray crystallography of four missense variants reveals how different mutations destabilize the protein fold and inhibit E2FTD or LxCxE binding. Taken together, this work provides the first understanding of the multiple ways through which stability, structure and function of Rbs pocket domain is altered by a large number of missense mutations seen in cancer.

biochemistry↗