Intrinsic crazes in polycarbonate: Phenomenology and molecular interpretation of a new phenomenon

Kinetochores are the chromosomal attachment points for spindle microtubules. They are also signaling hubs that control major cell cycle transitions and coordinate chromosome folding. Most well-studied eukaryotes rely on a conserved set of factors, which are divided among two loosely-defined groups, for these functions. Outer kinetochore proteins contact microtubules or regulate this contact directly. Inner kinetochore proteins designate the kinetochore assembly site by recognizing a specialized nucleosome containing the H3 variant Cse4/CENP-A. We previously determined the structure, resolved by cryo-electron microscopy (cryo-EM), of the yeast Ctf19 complex (Ctf19c, homologous to the vertebrate CCAN), providing a high-resolution view of inner kinetochore architecture (Hinshaw and Harrison, 2019). We now extend these observations by reporting a near-atomic model of the Ctf3 complex, the outermost Ctf19c sub-assembly seen in our original cryo-EM density. The model is sufficiently well-determined by the new data to enable molecular interpretation of Ctf3 recruitment and function.

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Molecular features underlying differential SHP1/SHP2 binding of immune checkpoint receptors

eLife ◽

10.7554/elife.74276 ◽

2021 ◽

Vol 10 ◽

Author(s):

Xiaozheng Xu ◽

Takeya Masubuchi ◽

Qixu Cai ◽

Yunlong Zhao ◽

Enfu Hui

Keyword(s):

T Cells ◽

Immune Checkpoint ◽

Large Family ◽

Side Chain ◽

Sh2 Domains ◽

Molecular Features ◽

Molecular Interpretation ◽

Parallel Mode ◽

Checkpoint Receptors ◽

Effector Binding

A large number of inhibitory receptors recruit SHP1 and/or SHP2, tandem-SH2-containing phosphatases, through phosphotyrosine-based motifs ITIM and ITSM. Despite the similarity, these receptors exhibit differential effector binding specificities, as exemplified by the immune checkpoint receptors PD-1 and BTLA, which preferentially recruit SHP2 and SHP1 respectively. The molecular basis by which structurally similar receptors discriminate SHP1 and SHP2 is unclear. Here, we provide evidence that human PD-1 and BTLA optimally bind to SHP1 and SHP2 via a bivalent, parallel mode that involves both SH2 domains of SHP1 or SHP2. PD-1 mainly uses its ITSM to prefer SHP2 over SHP1 via their C-terminal SH2 domains (cSH2): swapping SHP1-cSH2 with SHP2-cSH2 enabled PD-1:SHP1 association in T cells. In contrast, BTLA primarily utilizes its ITIM to prefer SHP1 over SHP2 via their N-terminal SH2 domains (nSH2). The ITIM of PD-1, however, appeared to be de-emphasized due to a glycine at pY+1 position. Substitution of this glycine with alanine, a residue conserved in BTLA and several SHP1-recruiting receptors, was sufficient to induce PD-1:SHP1 interaction in T cells. Finally, structural simulation and mutagenesis screening showed that SHP1 recruitment activity exhibits a bell-shaped dependence on the side chain volume of the pY+1 residue of ITIM. Collectively, we provide a molecular interpretation of the SHP1/SHP2-binding specificities of PD-1 and BTLA, with implications for the mechanisms of a large family of therapeutically relevant receptors.

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Selection of standard states in molecular interpretation of activity coefficients in fused salt solutions

Electrochimica Acta ◽

10.1016/0013-4686(69)85061-9 ◽

1969 ◽

Vol 14 (2) ◽

pp. 187-196

Author(s):

A. Kisza ◽

K. Gatner

Keyword(s):

Activity Coefficients ◽

Salt Solutions ◽

Molecular Interpretation ◽

Selection Of ◽

Standard States ◽

Fused Salt

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Different Distributions of Kinetically Apparent Molecular Varieties of α2-Macroglobulin in Health and in Patients with Cryptogenic Fibrosing Alveolitis

Clinical Science ◽

10.1042/cs0600261 ◽

1981 ◽

Vol 60 (3) ◽

pp. 261-265

Author(s):

R. M. Topping ◽

A. H. Craven ◽

Susan Whiting ◽

B. G. Rigden ◽

M. Turner-Warwick ◽

...

Keyword(s):

Protein Separation ◽

Proteinase Inhibitors ◽

Adult Population ◽

Kinetic Method ◽

Binding Modes ◽

Fibrosing Alveolitis ◽

Cryptogenic Fibrosing Alveolitis ◽

Α2 Macroglobulin ◽

Molecular Interpretation ◽

Proteinase Inhibition

1. Proteinase inhibitors have been studied in whole serum by using a kinetic method that avoids potentially damaging protein separation procedures. 2. The α2-macroglobulin of an individual can be allocated unambiguously into one of seven categories according to the binding of trypsin to inhibitor in two kinetically apparent binding modes (β- and α-modes). 3. The distribution of α2-macroglobulin β:α ratios in a healthy adult population is defined, and shown to be independent of sex and age. 4. The distribution of β: α ratios in a group of patients with cryptogenic fibrosing alveolitis was found to be significantly different (P < 0.005) from the normal distribution. 5. Changes in the β: α ratio were noted in five of six patients with cryptogenic fibrosing alveolitis after treatment, but on no occasion when two healthy subjects were assessed a total of nine times. 6. The molecular interpretation and the possible importance of altered proteinase inhibition in inflammation and fibrosis are discussed.

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