Description: The immunosuppressant and anticancer drug rapamycin works by inducing inhibitory protein complexes with the kinase mTOR, an important regulator of growth and proliferation. The obligatory accessory partner of rapamycin is believed to be FK506-binding protein 12 (FKBP12). Here we show that rapamycin complexes of larger FKBP family members can tightly bind to mTOR and potently inhibit its kinase activity. Cocrystal structures with FKBP51 and FKBP52 reveal the modified molecular binding mode of these alternative ternary complexes in detail. In cellular model systems, FKBP12 can be functionally replaced by larger FKBPs. When the rapamycin dosage is limiting, mTOR inhibition of S6K phosphorylation can be enhanced by FKBP51 overexpression in mammalian cells, whereas FKBP12 is dispensable. FKBP51 could also enable the rapamycin-induced hyperphosphorylation of Akt, which depended on higher FKBP levels than rapamycin-induced inhibition of S6K phosphorylation. These insights provide a mechanistic rationale for preferential mTOR inhibition in specific cell or tissue types by engaging specific FKBP homologs.

Description: A field intercomparison was conducted at the Acqua Alta Oceanographic Tower (AAOT) in the northern Adriatic Sea, from 9 to 19 July 2018 to assess differences in the accuracy of in- and above-water radiometer measurements used for the validation of ocean colour products. Ten measurement systems were compared. Prior to the intercomparison, the absolute radiometric calibration of all sensors was carried out using the same standards and methods at the same reference laboratory. Measurements were performed under clear sky conditions, relatively low sun zenith angles, moderately low sea state and on the same deployment platform and frame (except in-water systems). The weighted average of five above-water measurements was used as baseline reference for comparisons. For downwelling irradiance ( Ed ), there was generally good agreement between sensors with differences of 〈6% for most of the sensors over the spectral range 400 nm–665 nm. One sensor exhibited a systematic bias, of up to 11%, due to poor cosine response. For sky radiance ( Lsky ) the spectrally averaged difference between optical systems was 〈2.5% with a root mean square error (RMS) 〈0.01 mWm−2 nm−1 sr−1. For total above-water upwelling radiance ( Lt ), the difference was 〈3.5% with an RMS 〈0.009 mWm−2 nm−1 sr−1. For remote-sensing reflectance ( Rrs ), the differences between above-water TriOS RAMSES were 〈3.5% and 〈2.5% at 443 and 560 nm, respectively, and were 〈7.5% for some systems at 665 nm. Seabird-Hyperspectral Surface Acquisition System (HyperSAS) sensors were on average within 3.5% at 443 nm, 1% at 560 nm, and 3% at 665 nm. The differences between the weighted mean of the above-water and in-water systems was 〈15.8% across visible bands. A sensitivity analysis showed that Ed accounted for the largest fraction of the variance in Rrs , which suggests that minimizing the errors arising from this measurement is the most important variable in reducing the inter-group differences in Rrs . The differences may also be due, in part, to using five of the above-water systems as a reference. To avoid this, in situ normalized water-leaving radiance ( Lwn ) was therefore compared to AERONET-OC SeaPRiSM Lwn as an alternative reference measurement. For the TriOS-RAMSES and Seabird-HyperSAS sensors the differences were similar across the visible spectra with 4.7% and 4.9%, respectively. The difference between SeaPRiSM Lwn and two in-water systems at blue, green and red bands was 11.8%. This was partly due to temporal and spatial differences in sampling between the in-water and above-water systems and possibly due to uncertainties in instrument self-shading for one of the in-water measurements.