Browsing by Subject "CONTACTS"

Sort by: Order: Results:

Now showing items 1-3 of 3
  • Xu, Yingying; Puranen, Santeri; Corander, Jukka; Kabashima, Yoshiyuki (2018)
    We propose an efficient procedure for significance determination in high-dimensional dependence learning based on surrogate data testing, termed inverse finite-size scaling (IFSS). The IFSS method is based on our discovery of a universal scaling property of random matrices which enables inference about signal behavior from much smaller scale surrogate data than the dimensionality of the original data. As a motivating example, we demonstrate the procedure for ultra-high-dimensional Potts models with order of 1010 parameters. IFSS reduces the computational effort of the data-testing procedure by several orders of magnitude, making it very efficient for practical purposes. This approach thus holds considerable potential for generalization to other types of complex models.
  • Santinho, Alexandre; Salo, Veijo T.; Chorlay, Aymeric; Li, Shiqian; Zhou, Xin; Omrane, Mohyeddine; Ikonen, Elina; Thiam, Abdou Rachid (2020)
    Lipid droplet (LD) biogenesis begins in the endoplasmic reticulum (ER) bilayer, but how the ER topology impacts this process is unclear. An early step in LD formation is nucleation, wherein free neutral lipids, mainly triacylglycerols (TGs) and sterol esters (SEs), condense into a nascent LD. How this transition occurs is poorly known. Here, we found that LDs preferably assemble at ER tubules, with higher curvature than ER sheets, independently of the LD assembly protein seipin. Indeed, the critical TG concentration required for initiating LD assembly is lower at curved versus flat membrane regions. In agreement with this finding, flat ER regions bear higher amounts of free TGs than tubular ones and present less LDs. By using an in vitro approach, we discovered that the presence of free TGs in tubules is energetically unfavorable, leading to outflow of TGs to flat membrane regions or condensation into LDs. Accordingly, in vitro LD nucleation can be achieved by the sole increase of membrane curvature. In contrast to TGs, the presence of free SEs is favored at tubules and increasing SE levels is inhibitory to the curvature-induced nucleation of TG LDs. Finally, we found that seipin is enriched at ER tubules and controls the condensation process, preventing excessive tubule-induced nucleation. The absence of seipin provokes erratic LD nucleation events determined by the abundance of ER tubules. In summary, our data indicate that membrane curvature catalyzes LD assembly.
  • Prasanna, Xavier; Salo, Veijo Tuomas; Li, Shiqian; Ven, Katharina; Vihinen, Helena; Jokitalo, Eija; Vattulainen, Ilpo; Ikonen, Elina (2021)
    Seipin is a disk-like oligomeric endoplasmic reticulum (ER) protein important for lipid droplet (LD) biogenesis and triacylglycerol (TAG) delivery to growing LDs. Here we show through biomolecular simulations bridged to experiments that seipin can trap TAGs in the ER bilayer via the luminal hydrophobic helices of the protomers delineating the inner opening of the seipin disk. This promotes the nanoscale sequestration of TAGs at a concentration that by itself is insufficient to induce TAG clustering in a lipid membrane. We identify Ser166 in the alpha 3 helix as a favored TAG occupancy site and show that mutating it compromises the ability of seipin complexes to sequester TAG in silico and to promote TAG transfer to LDs in cells. While the S166D-seipin mutant colocalizes poorly with promethin, the association of nascent wild-type seipin complexes with promethin is promoted by TAGs. Together, these results suggest that seipin traps TAGs via its luminal hydrophobic helices, serving as a catalyst for seeding the TAG cluster from dissolved monomers inside the seipin ring, thereby generating a favorable promethin binding interface.