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Comment: 9 pages, including 3 figures; accepted for publication in the Astrophysical Journal
Soluble N-ethylmaleimide sensitive factor-attachment protein receptors (SNAREs) and Sec1p/Munc18-homologs (SM proteins) play key roles in intracellular membrane fusion. The SNAREs form tight four-helix bundles (core complexes) that bring the membranes together, but it is unclear how this activity is coupled to SM protein function. Studies of the yeast trans-Golgi network (TGN)/endosomal SNARE complex, which includes the syntaxin-like SNARE Tlg2p, have suggested that its assembly requires activation by binding of the SM protein Vps45p to the cytoplasmic region of Tlg2p folded into a closed conformation. Nuclear magnetic resonance and biochemical experiments now show that Tlg2p and Pep12p, a late- endosomal syntaxin that interacts functionally but not directly with Vps45p, have a domain structure characteristic of syntaxins but do not ad...
Clinically useful predictors of the efficacy of adjuvant chemotherapy following curative colorectal surgery remain to be determined. In the present study, we investigated the clinical utility of the collagen gel droplet-embedded culture drug sensitivity test (CD-DST) as a predictor of the therapeutic response to 5-fluorouracil (5-FU)-based adjuvant chemo-therapy in patients with stage II–III colorectal cancer. CD-DST was conducted using tumor samples surgically obtained from 189 patients. The therapeutic effect of 5-FU-based regimens between high (high-group) and low (low-group) sensitivity groups and a group that did not receive chemotherapy [CTx(-) group] was compared. CD-DST was successfully performed in 151 out of the 189 patients (79.9%), 87 of whom received 5-FU-based adjuvant chemotherapy after surgery. Twenty-seven of these 87 ...
Sec1/Munc18-like (SM) proteins functionally interact with soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) in membrane fusion, but the mechanisms of these interactions differ. In vertebrates, SM proteins that mediate exocytosis (Munc18-1, 18-2, and 18c) bind to the closed conformation of syntaxins 1–4, which requires the N-terminal Habc domains and SNARE motifs of these syntaxins. In contrast, SM proteins that mediate Golgi and endoplasmic reticulum fusion (Sly1 and Vps45) bind only to short N-terminal sequences of syntaxins 5, 16, or 18, independently of their Habc domains and SNARE motifs. We now show that Munc18-1, Sly1, and Vps45 interact with cognate syntaxins via similar, autonomously folded N-terminal domains, but the syntaxin 5-binding surface of the Sly1 N-terminal domain is opposite to the syntax...
P-glycoprotein exports various hydrophobic chemicals in an ATP-dependent manner, determines their absorption and distribution in the body, and is involved in multidrug resistance (MDR) in tumors. Understanding the mechanism of the multidrug transport is important for designing drugs of good bioavailability and efficient cancer chemotherapy. We determined the high-resolution crystal structures of a eukaryotic P-glycoprotein homolog and revealed the detailed architecture of its transmembrane domains, which contain an exit gate for substrates that opens to the extracellular side and two entrance gates that open to the intramembranous region and the cytosolic side. We propose a motion of the transmembrane domains powered by the association of two nucleotide-binding domains on ATP binding that is different from other transporters.
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