Intramolecular Cohesion of Coils Mediated by Phenylalanine–Glycine Motifs in the Natively Unfolded Domain of a Nucleoporin

The nuclear pore complex (NPC) provides the sole aqueous conduit for macromolecular exchange between the nucleus and the cytoplasm of cells. Its diffusion conduit contains a size-selective gate formed by a family of NPC proteins that feature large, natively unfolded domains with phenylalanine–glycine repeats (FG domains). These domains of nucleoporins play key roles in establishing the NPC permeability barrier, but little is known about their dynamic structure. Here we used molecular modeling and biophysical techniques to characterize the dynamic ensemble of structures of a representative FG domain from the yeast nucleoporin Nup116. The results showed that its FG motifs function as intramolecular cohesion elements that impart order to the FG domain and compact its ensemble of structures into native premolten globular configurations. At the NPC, the FG motifs of nucleoporins may exert this cohesive effect intermolecularly as well as intramolecularly to form a malleable yet cohesive quaternary structure composed of highly flexible polypeptide chains. Dynamic shifts in the equilibrium or competition between intra- and intermolecular FG motif interactions could facilitate the rapid and reversible structural transitions at the NPC conduit needed to accommodate passing karyopherin–cargo complexes of various shapes and sizes while simultaneously maintaining a size-selective gate against protein diffusion

Towards reconciling structure and function in the nuclear pore complex

The spatial separation between the cytoplasm and the cell nucleus necessitates the continuous exchange of macromolecular cargo across the double-membraned nuclear envelope. Being the only passageway in and out of the nucleus, the nuclear pore complex (NPC) has the principal function of regulating the high throughput of nucleocytoplasmic transport in a highly selective manner so as to maintain cellular order and function. Here, we present a retrospective review of the evidence that has led to the current understanding of both NPC structure and function. Looking towards the future, we contemplate on how various outstanding effects and nanoscopic characteristics ought to be addressed, with the goal of reconciling structure and function into a single unified picture of the NPC

Spatial organization of the nucleus compartmentalizes and regulates the genome

The nucleus must simultaneously orchestrate DNA replication, transcription, splicing, signalling, and directional transport of proteins into the nucleus and RNA out of the nucleus. Yet the nucleus has no internal membranes to compartmentalize these functions as the cytoplasm does. In fact, such compartmentalization would necessarily be detrimental because particular genes at different locations on the linear chromosomes need to be made at different times while others on the same chromosome need to be tightly shut off. Moreover, expressed genes need to be accessible to a feedback mechanism to determine when to modulate transcription. To accommodate these additional needs the nucleus appears to form microdomains by co-assembly of functional complexes. Thus, microdomains can either form around activated regions on a chromosome or regions on a linear chromosome could be fed into such microdomains for activation. Findings that genome encoded regulatory elements such as enhancers can be hundreds of kb and even Mb apart further highlights the need for such a system as these distal elements must come together in the 3D space of the genome for their efficient functioning. While this much is understood, there is much still to be learned about mechanisms that the nucleus uses to regulate the genome and much more to be learned about how these microdomains come into being. As there is no stable structure within the nucleus except for the nuclear envelope, much recent research has been focusing on potential roles of this subnuclear organelle in establishing 3D nuclear architecture and orchestrating the regulation of these various functions

Physical function and quality of life in patients with chronic graft-versus-host-disease: A summary of preclinical and clinical studies and a call for exercise intervention trials in patients

Allogeneic Hematopoietic Stem Cell Transplant, to reconstitute hematopoietic and immune status of patients undergoing myeloablative therapy for hematologic disorders, has been of great benefit in minimizing or eradicating disease and extending survival. Patients who undergo allogeneic hematopoietic stem cell transplant (allo-HSCT) are subject to many comorbidities among which the most significant, affecting quality of life (QoL) and survival, are acute (aGVHD) and chronic Graft Versus Host Disease (cGVHD), resulting from donor lymphocytes reacting to and damaging host tissues. Physical activity and exercise have clearly been shown, in both children and adults, to enhance fitness, improve symptomatology and QoL, reduce disease progression and extend survival for many diseases including malignancies. In some cases, vigorous exercise has been shown to be equal to or more effective than pharmacologic therapy. This review addresses how cGVHD affects patients’ physical function and physical domain of QoL, and the potential benefits of exercise interventions along with recommendations for relevant research and evaluation targeted at incorporating this strategy as soon as possible after allo-HSCT and ideally, as soon as possible upon diagnosis of the condition leading to allo-HSCT.Sin financiación3.874 JCR (2016) Q2, 20/70 Hematology, 48/151 Immunology, 71/217 Oncology, 7/25 Transplantation1.986 SJR (2016) Q1, 18/135 Hematology, 5/42 TransplantationNo data IDR 2016UE