Modeling the Structure of Keratin 1 and 10 Terminal Domains and their Misassembly in Keratoderma.

The terminal domains of suprabasal keratins of the skin epithelium are very resistant to evidence-based structural analysis because of their inherent flexibility and lack of predictable structure. We present a model for the structure and interactions of the head and tail domains of epidermal keratins 1 and 10, based on all-atom 3D simulations of keratin primary amino acid sequences, and tyrosine phosphorylation predictions, extracted from published databases. We observed that keratin 1 and 10 end domains are likely to form a tetrameric terminal domain complex incorporating a reversibly extendable region potentially acting as a molecular spring.

Mechanisms of resistance and adaptation to thapsigargin in androgen-independent prostate cancer PC3 and DU145 cells.

Cells with increasing resistance to the sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase (SERCA) inhibitor thapsigargin (TG), ranging from 60-fold (PC3/TG(10) cells) to 1350-fold (PC3/TG(2000) cells), were derived from PC3 cells. SERCA2 is overexpressed in all PC3/TG cells but retains sensitivity to TG. siRNA-mediated downregulation of SERCA completely or partially reverses TG resistance in PC3/TG(10) or PC3/TG(2000) cells, respectively; thus SERCA overexpression mediates resistance in PC3/TG(10) cells but is not the only resistance mechanism in PC3/TG(2000) cells.