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

J. Appl. Cryst.の発刊に際して

The Heat Shock Response: Life on the Verge of Death

The molecular chaperone heat shock protein 90 (HSP90) has been used by cancer cells to facilitate the function of numerous oncoproteins, and it can be argued that cancer cells are 'addicted' to HSP90. However, although recent reports of the early clinical efficacy of HSP90 inhibitors are encouraging, the optimal use of HSP90-targeted therapeutics will depend on understanding the complexity of HSP90 regulation and the degree to which HSP90 participates in both neoplastic and normal cellular physiology.

/pdf/targeting-the-dynamic-hsp90-complex-in-cancer-3g1j2py0i7.pdf

Targeting the dynamic HSP90 complex in cancer

https://www.cell.com/developmental-cell/pdf/S1534-5807(11)00207-3.pdf

The ESCRT Pathway

The ATPase cycle of the mitochondrial Hsp90 analog Trap1.

Coupling and dynamics of subunits in the hexameric AAA+ chaperone ClpB.

Repeat proteins are composed of tandem arrays of 30- to 40-residue structural motifs and are characterized by short-range interactions between residues close in sequence. Here we have investigated the equilibrium unfolding of D34, a 426-residue fragment of ankyrinR that comprises 12 ankyrin repeats. We show that D34 unfolds via an intermediate in which the C-terminal half of the protein is structured and the N-terminal half is unstructured. Surprisingly, however, we find that we change the unfolding process when we attempt to probe it. Single-site, moderately destabilizing mutations at the C terminus result in different intermediates dominating. The closer to the C terminus the mutation, the fewer repeats are structured in the intermediate; thus, structure in the intermediate frays from the site of the mutation. This behavior contrasts with the robust unfolding of globular proteins in which mutations can destabilize an intermediate but do not cause a different intermediate to be populated. We suggest that, for large repeat arrays, the energy landscape is very rough, with many different low-energy species containing varying numbers of folded modules so the species that dominates can be altered easily by single, conservative mutations. The multiplicity of partly folded states populated in the equilibrium unfolding of D34 is also mirrored by the kinetic folding mechanism of ankyrin-repeat proteins in which we have observed that parallel pathways are accessible from different initiation sites in the structure.

https://www.pnas.org/content/pnas/104/19/7863.full.pdf

Probing a moving target with a plastic unfolding intermediate of an ankyrin-repeat protein

The 33-amino-acid ankyrin motif comprises a β-turn followed by two anti-parallel α-helices and a loop and tandem arrays of the motif pack in a linear fashion to produce elongated structures characterized by short-range interactions. In this article we use site-directed mutagenesis to investigate the kinetic unfolding mechanism of D34, a 426-residue, 12-ankyrin repeat fragment of the protein ankyrinR. The data are consistent with a model in which the N-terminal half of the protein unfolds first by unraveling progressively from the start of the polypeptide chain to form an intermediate; in the next step, the C-terminal half of the protein unfolds via two pathways whose transition states have either the early or the late C-terminal ankyrin repeats folded. We conclude that the two halves of the protein unfold by different mechanisms because the N-terminal moiety folds and unfolds in the context of a folded C-terminal moiety, which therefore acts as a “seed” and confers a unique directionality on the process, whereas the C-terminal moiety folds and unfolds in the context of an unfolded N-terminal moiety and therefore behaves like a single-domain ankyrin repeat protein, having a high degree of symmetry and consequently more than one unfolding pathway accessible to it.

Nicolas D. Werbeck

Papers

The ATPase cycle of the mitochondrial Hsp90 analog Trap1.

Coupling and dynamics of subunits in the hexameric AAA+ chaperone ClpB.

Probing a moving target with a plastic unfolding intermediate of an ankyrin-repeat protein

Shifting transition states in the unfolding of a large ankyrin repeat protein

Disaggregases in 4 dimensions