Key steps in unconventional secretion of fibroblast growth factor 2 reconstituted with purified components

نویسندگان

  • Julia P Steringer
  • Sascha Lange
  • Sabína Čujová
  • Radek Šachl
  • Chetan Poojari
  • Fabio Lolicato
  • Oliver Beutel
  • Hans-Michael Müller
  • Sebastian Unger
  • Ünal Coskun
  • Alf Honigmann
  • Ilpo Vattulainen
  • Martin Hof
  • Christian Freund
  • Walter Nickel
چکیده

FGF2 is secreted from cells by an unconventional secretory pathway. This process is mediated by direct translocation across the plasma membrane. Here, we define the minimal molecular machinery required for FGF2 membrane translocation in a fully reconstituted inside-out vesicle system. FGF2 membrane translocation is thermodynamically driven by PI(4,5)P2-induced membrane insertion of FGF2 oligomers. The latter serve as dynamic translocation intermediates of FGF2 with a subunit number in the range of 8-12 FGF2 molecules. Vectorial translocation of FGF2 across the membrane is governed by sequential and mutually exclusive interactions with PI(4,5)P2 and heparan sulfates on opposing sides of the membrane. Based on atomistic molecular dynamics simulations, we propose a mechanism that drives PI(4,5)P2 dependent oligomerization of FGF2. Our combined findings establish a novel type of self-sustained protein translocation across membranes revealing the molecular basis of the unconventional secretory pathway of FGF2.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

The unconventional secretory machinery of fibroblast growth factor 2.

Unconventional secretory proteins represent a subpopulation of extracellular factors that are exported from eukaryotic cells by mechanisms that do not depend on the endoplasmic reticulum and the Golgi complex. Various pathways have been implicated in unconventional secretion including those involving intracellular membrane-bound intermediates and others that are based on direct protein transloc...

متن کامل

Active Caspase-1 Is a Regulator of Unconventional Protein Secretion

Mammalian cells export most proteins by the endoplasmic reticulum/Golgi-dependent pathway. However, some proteins are secreted via unconventional, poorly understood mechanisms. The latter include the proinflammatory cytokines interleukin(IL)-1beta, IL-18, and IL-33, which require activation by caspase-1 for biological activity. Caspase-1 itself is activated by innate immune complexes, the infla...

متن کامل

Unconventional secretion of fibroblast growth factor 2--a novel type of protein translocation across membranes?

N-terminal signal peptides are a hallmark of the vast majority of soluble secretory proteins that are transported along the endoplasmic reticulum/Golgi-dependent pathway. They are recognized by signal recognition particle, a process that initiates membrane translocation into the lumen of the endoplasmic reticulum followed by vesicular transport to the cell surface and release into the extracell...

متن کامل

Unconventional Protein Secretion in Animal Cells.

All eukaryotic cells secrete a range of proteins in a constitutive or regulated manner through the conventional or canonical exocytic/secretory pathway characterized by vesicular traffic from the endoplasmic reticulum, through the Golgi apparatus, and towards the plasma membrane. However, a number of proteins are secreted in an unconventional manner, which are insensitive to inhibitors of conve...

متن کامل

Unconventional protein secretion: membrane translocation of FGF-2 does not require protein unfolding.

Endoplasmic reticulum/Golgi-dependent protein secretion depends on signal peptides that mediate membrane translocation of nascent secretory proteins into the lumen of the endoplasmic reticulum. Classical secretory proteins are transported across the membrane of the endoplasmic reticulum in an unfolded conformation, which is similar to protein import into mitochondria. This process is mediated b...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:

دوره 6  شماره 

صفحات  -

تاریخ انتشار 2017