A Structural Model of the Sgt2 Protein and Its Interactions with Chaperones and the Get4/Get5 Complex

The insertion of tail-anchored transmembrane (TA) proteins into the appropriate membrane is a post-translational event that requires stabilization of the transmembrane domain and targeting to the proper destination. Sgt2 is a heat-shock protein cognate (HSC) co-chaperone that preferentially binds endoplasmic reticulum-destined TA proteins and directs them to the GET pathway via Get4 and Get5. Here, we present the crystal structure from a fungal Sgt2 homolog of the tetratrico-repeat (TPR) domain and part of the linker that connects to the C-terminal domain. The linker extends into the two-carboxylate clamp of the TPR domain from a symmetry-related molecule mimicking the binding to HSCs. Based on this structure, we provide biochemical evidence that the Sgt2 TPR domain has the ability to directly bind multiple HSC family members. The structure allows us to propose features involved in this lower specificity relative to other TPR containing co-chaperones. We further show that a dimer of Sgt2 binds a single Get5 and use small angle x-ray scattering to characterize the domain arrangement of Sgt2 in solution. These results allow us to present a structural model of the Sgt2-Get4/Get5-HSC complex

Inteligencias Múltiples en Estudiantes de Primer año de Medicina de una Universidad Venezolana

People learn and use knowledge in different ways, applying new alternatives. We studied how multiple intelligences were manifested in the students of the first year of medicine at the University of Carabobo. 215 students from the first year of medicine were assessed using the adult multiple intelligences inventory designed by Armstrong. It was found that students achieved high scores in Visual spatial intelligence (55.8%); Bodily Kynesthetic learning (69.8%); Musical learning (46.5%) and Intrapersonal learning (69.8%). We conclude that respondents recognize its strengths, weaknesses and establish objectives. Were reflexive, had sound reasoning and were able to to make recommendations to their friends and family, they also like to work alone and follow their own interests. We recommend that educational curricula will not only focus on the predominance of linguistic and mathematical intelligence, thus changing the form of assessment.Las personas aprenden y utilizan el saber de diferentes modos, aplicando nuevas alternativas. Se estudió cómo se manifiestan las inteligencias múltiples en los estudiantes del primer año de Medicina, de la Universidad de Carabobo. Metodología descriptiva, transversal en una muestra probabilística de 215 estudiantes del primer año de medicina mediante el Inventario de Inteligencias Múltiples para adultos diseñado por Armstrong. Se encontró que los alumnos alcanzaron puntajes Muy altos, en Inteligencia Visual Espacial (55,8%); Corporal Kinestésico (69,8%); Musical Auditiva (46,5%) e Intrapersonal (69,8%). Se concluye que los encuestados reconocen sus puntos fuertes, sus debilidades y establecen objetivos. Son reflexivos, poseen razonamiento acertado y son capaces de aconsejar amigos y familiares, pero les gusta trabajar solos y seguir sus intereses. Se recomienda seguir con esta línea de investigación sugiriendo que los programas de enseñanza no sólo se concentren en el predominio de inteligencia lingüística y matemática, cambiando la forma de evaluación

Structure of the Escherichia coli ProQ RNA-binding protein

The protein ProQ has recently been identified as a global small noncoding RNA-binding protein in Salmonella, and a similar role is anticipated for its numerous homologs in divergent bacterial species. We report the solution structure of Escherichia call ProQ, revealing an N-terminal FinO-like domain, a C-terminal domain that unexpectedly has a Tudor domain fold commonly found in eukaryotes, and an elongated bridging intradomain linker that is flexible but nonetheless incompressible. Structure-based sequence analysis suggests that the Tudor domain was acquired through horizontal gene transfer and gene fusion to the ancestral FinO-like domain. Through a combination of biochemical and biophysical approaches, we have mapped putative RNA-binding surfaces on all three domains of ProQ and modeled the protein's conformation in the apo and RNA-bound forms. Taken together, these data suggest how the FinO, Tudor, and linker domains of ProQ cooperate to recognize complex RNA structures and serve to promote RNA-mediated regulation

Structural insights into RapZ-mediated regulation of bacterial amino-sugar metabolism

In phylogenetically diverse bacteria, the conserved protein RapZ plays a central role in RNA-mediated regulation of amino-sugar metabolism. RapZ contributes to the control of glucosamine phosphate biogenesis by selectively presenting the regulatory small RNA GlmZ to the essential ribonuclease RNase E for inactivation. Here, we report the crystal structures of full length Escherichia coli RapZ at 3.40 Å and 3.25 Å, and its isolated C-terminal domain at 1.17 Å resolution. The structural data confirm that the N-terminal domain of RapZ possesses a kinase fold, whereas the C-terminal domain bears closest homology to a subdomain of 6-phosphofructokinase, an important enzyme in the glycolytic pathway. RapZ self-associates into a domain swapped dimer of dimers, and in vivo data support the importance of quaternary structure in RNA-mediated regulation of target gene expression. Based on biochemical, structural and genetic data, we suggest a mechanism for binding and presentation by RapZ of GlmZ and the closely related decoy sRNA, GlmY. We discuss a scenario for the molecular evolution of RapZ through re-purpose of enzyme components from central metabolism.© The Author(s) 201

Comprehensive virtual screening of 4.8 k flavonoids reveals novel insights into allosteric inhibition of SARS-CoV-2 M^PRO

El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado.SARS-CoV-2 main protease is a common target for inhibition assays due to its high conservation among coronaviruses. Since flavonoids show antiviral activity, several in silico works have proposed them as potential SARS-CoV-2 main protease inhibitors. Nonetheless, there is reason to doubt certain results given the lack of consideration for flavonoid promiscuity or main protease plasticity, usage of short library sizes, absence of control molecules and/or the limitation of the methodology to a single target site. Here, we report a virtual screening study where dorsilurin E, euchrenone a11, sanggenol O and CHEMBL2171598 are proposed to inhibit main protease through different pathways. Remarkably, novel structural mechanisms were observed after sanggenol O and CHEMBL2171598 bound to experimentally proven allosteric sites. The former drastically affected the active site, while the latter triggered a hinge movement which has been previously reported for an inactive SARS-CoV main protease mutant. The use of a curated database of 4.8 k flavonoids, combining two well-known docking software (AutoDock Vina and AutoDock4.2), molecular dynamics and MMPBSA, guaranteed an adequate analysis and robust interpretation. These criteria can be considered for future screening campaigns against SARS-CoV-2 main protease.Consejo Nacional de Ciencia, Tecnología e Innovación TecnológicaRevisión por pare