There is, I think, something ethereal about i —the square root of minus one. I remember first hearing about it at school. It seemed an odd beast at that time—an intruder hovering on the edge of reality.

Usually familiarity dulls this sense of the bizarre, but in the case of i it was the reverse: over the years the sense of its surreal nature intensified. It seemed that it was impossible to write mathematics that described the real world in …

I and i

抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Efficient folding of many newly synthesized proteins depends on assistance from molecular chaperones, which serve to prevent protein misfolding and aggregation in the crowded environment of the cell. Nascent chain–binding chaperones, including trigger factor, Hsp70, and prefoldin, stabilize elongating chains on ribosomes in a nonaggregated state. Folding in the cytosol is achieved either on controlled chain release from these factors or after transfer of newly synthesized proteins to downstream chaperones, such as the chaperonins. These are large, cylindrical complexes that provide a central compartment for a single protein chain to fold unimpaired by aggregation. Understanding how the thousands of different proteins synthesized in a cell use this chaperone machinery has profound implications for biotechnology and medicine.

https://science.sciencemag.org/content/sci/295/5561/1852.full.pdf

Molecular Chaperones in the Cytosol: from Nascent Chain to Folded Protein

Most proteins must fold into defined three-dimensional structures to gain functional activity. But in the cellular environment, newly synthesized proteins are at great risk of aberrant folding and aggregation, potentially forming toxic species. To avoid these dangers, cells invest in a complex network of molecular chaperones, which use ingenious mechanisms to prevent aggregation and promote efficient folding. Because protein molecules are highly dynamic, constant chaperone surveillance is required to ensure protein homeostasis (proteostasis). Recent advances suggest that an age-related decline in proteostasis capacity allows the manifestation of various protein-aggregation diseases, including Alzheimer's disease and Parkinson's disease. Interventions in these and numerous other pathological states may spring from a detailed understanding of the pathways underlying proteome maintenance.

/pdf/molecular-chaperones-in-protein-folding-and-proteostasis-ou781oriq0.pdf

Molecular chaperones in protein folding and proteostasis

Hsp70 proteins are central components of the cellular network of molecular chaperones and folding catalysts. They assist a large variety of protein folding processes in the cell by transient association of their substrate binding domain with short hydrophobic peptide segments within their substrate proteins. The substrate binding and release cycle is driven by the switching of Hsp70 between the low-affinity ATP bound state and the high-affinity ADP bound state. Thus, ATP binding and hydrolysis are essential in vitro and in vivo for the chaperone activity of Hsp70 proteins. This ATPase cycle is controlled by co-chaperones of the family of J-domain proteins, which target Hsp70s to their substrates, and by nucleotide exchange factors, which determine the lifetime of the Hsp70-substrate complex. Additional co-chaperones fine-tune this chaperone cycle. For specific tasks the Hsp70 cycle is coupled to the action of other chaperones, such as Hsp90 and Hsp100.

/pdf/hsp70-chaperones-cellular-functions-and-molecular-mechanism-lfkzg6qhex.pdf

Hsp70 chaperones: cellular functions and molecular mechanism.

Impaired interdomain communication in mitochondrial Hsp70 results in the loss of inward-directed translocation force.

All cellular processes depend on the functionality of proteins. Although the functionality of a given protein is the direct consequence of its unique amino acid sequence, it is only realized by the folding of the polypeptide chain into a single defined three-dimensional arrangement or more commonly into an ensemble of interconverting conformations. Investigating the connection between protein conformation and its function is therefore essential for a complete understanding of how proteins are able to fulfill their great variety of tasks. One possibility to study conformational changes a protein undergoes while progressing through its functional cycle is hydrogen-1H/2H-exchange in combination with high-resolution mass spectrometry (HX-MS). HX-MS is a versatile and robust method that adds a new dimension to structural information obtained by e.g. crystallography. It is used to study protein folding and unfolding, binding of small molecule ligands, protein-protein interactions, conformational changes linked to enzyme catalysis, and allostery. In addition, HX-MS is often used when the amount of protein is very limited or crystallization of the protein is not feasible. Here we provide a general protocol for studying protein dynamics with HX-MS and describe as an example how to reveal the interaction interface of two proteins in a complex.

/pdf/analyzing-protein-dynamics-using-hydrogen-exchange-mass-5kuko1k5az.pdf

Analyzing protein dynamics using hydrogen exchange mass spectrometry.

Light-induced differences in conformational dynamics of the circadian clock regulator VIVID.

Phosphotyrosine confers client specificity to Hsp90.

The Hsp70 Ssb serves a dual role in de novo protein folding and ribosome biogenesis; however, the mechanism by which Ssb affects ribosome production is unclear. Here we establish that Ssb is causally linked to the regulation of ribosome biogenesis via the TORC1-Sch9 signaling pathway. Ssb is bound to Sch9 posttranslationally and required for the TORC1-dependent phosphorylation of Sch9 at T737. Also, Sch9 lacking phosphorylation at T737 displays significantly reduced kinase activity with respect to targets involved in the regulation of ribosome biogenesis. The absence of either Ssb or Sch9 causes enhanced ribosome aggregation. Particularly with respect to proper assembly of the small ribosomal subunit, SSB and SCH9 display strong positive genetic interaction. In combination, the data indicate that Ssb promotes ribosome biogenesis not only via cotranslational protein folding, but also posttranslationally via interaction with natively folded Sch9, facilitating access of the upstream kinase TORC1 to Sch9-T737. The yeast Hsp70 homolog Ssb is a chaperone that binds translating ribosomes where it is thought to function primarily by promoting nascent peptide folding. Here the authors find that the ribosome biogenesis defect associated with the loss of Ssb is attributable to a specific disruption in TORC1 signaling rather than defects in ribosomal protein folding.

/pdf/the-hsp70-homolog-ssb-affects-ribosome-biogenesis-via-the-4nhixqxwye.pdf

Matthias P. Mayer

Papers

Impaired interdomain communication in mitochondrial Hsp70 results in the loss of inward-directed translocation force.

Analyzing protein dynamics using hydrogen exchange mass spectrometry.

Light-induced differences in conformational dynamics of the circadian clock regulator VIVID.

Phosphotyrosine confers client specificity to Hsp90.

The Hsp70 homolog Ssb affects ribosome biogenesis via the TORC1-Sch9 signaling pathway