1231 Reducing the dimensionality of the protein folding-search problem
George D. Chellapa and George D. Rose
The protein folding search problem is concerned with the way a folding protein negotiates the vastness of conformational space en route to its native structure. It's a hard problem for computational biologists (though not for proteins) because three-dimensional space is complex. Here, the authors transform the problem into a simpler one-dimensional representation, one well adapted for use with readily available, sequence-based search algorithms, such as BLAST. Chellapa and Rose also note that the conventional representation of conformational space, exemplified by Levinthal's famous back-of-the-envelope calculation, ignores a dramatic and simplifying degeneracy, that is, built into the physical chemistry of the protein backbone.
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1113 Effect of thermal stability on protein adsorption to silica using homologous aldo-keto reductases
Flora Felsovalyi, Tushar Patel, Paolo Mangiagalli, Sanat K. Kumar, and Scott Banta
The adsorption of proteins to solid surfaces is dependent on many variables including charge differences, protein hydrophobicity, and protein stability. To address the importance of stability, the adsorption and desorption of two homologous proteins with dramatically different intrinsic stabilities were investigated. It is often assumed that more stable proteins will be less prone to surface-induced conformational changes. However in this study, the increase in stability did not have a profound effect on the adsorption or desorption behavior of the proteins, suggesting other factors likely dominate this process.
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1172 Cysteine-rich domains related to Frizzled receptors and Hedgehog interacting proteins
Jimin Pei and Nick V. Grishin
Frizzled receptors possess an extracellular cysteine-rich domain (FZ-CRD) that binds the Wnt ligands. Domains distantly related to FZ-CRDs, in Hedgehog-interacting proteins (HHIPs), folate receptors and riboflavin-binding proteins (FRBPs), and Niemann-Pick type C1 proteins (NPC1s), referred to as HFN-CRDs, exhibit similar yet distinct disulfide connectivity patterns compared to FZ-CRDs. Sequence similarity searches expanded the set of FZ-CRDs to include members from plants and various protists. Moreover, two new groups of divergent FZ-CRDs were identified: one in fungal calcium channel component MID1 and the other in metazoan RECK proteins. Structural comparisons revealed a unique HFN-CRD in glypicans (figure: the CRD of human glypican-1 with six disulfide bonds shown in magenta), a family of heparan sulfate proteoglycans that modulate the functions of morphogens including Wnts and Hedgehogs.
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1138 Structural and functional characterization of the interaction of the photosensitizing probe methylene blue with Torpedo californica acetylcholinesterase
Aviv Paz, Esther Roth, Yacov Ashani, Yechun Xu, Valery L. Shnyrov, Joel L. Sussman, Israel Silman, and Lev Weiner
The photosensitizer, methylene blue, has multiple medical applications, including photodynamic therapy (PDT), due to its capacity to generate the powerful oxidizing agent, singlet oxygen. In the dark, it reversibly inhibits Torpedo acetylcholinesterase, but under illumination, the singlet oxygen generated produces irreversible inactivation. The enzyme's active site is near the bottom of a deep and narrow gorge. The crystal structure of its methylene blue complex reveals a single dye molecule within the gorge stacked against the indole of conserved Trp279; it is plausible that irreversible inhibition is associated with photo-oxidation of this residue. Our data demonstrate that acetylcholinesterase provides a valuable model for understanding the molecular basis of local photo-oxidative damage.
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