An endosomal escort

Transmembrane proteins and lipids are delivered to the endosomal lumen by the multivesicular-body sorting pathway — a pathway that is important for receptor downregulation and viral budding. The sorting process requires a ubiquitin signal and the transfer of ubiquitylated cargo between the protein complexes ESCRT-I, -II and -III (endosomal sorting complexes required for transport). And now, in Nature, Hurley and colleagues provide valuable insights into this process by describing the 3.6-Å-resolution crystal structure of the core of yeast ESCRT-II.

ESCRT-II is composed of Vps22 (vacuolar protein sorting-22), Vps36 and two molecules of Vps25, and the core structure is a rigid 'Y' shape. One molecule of Vps25 forms the base of the Y, the second forms a branch, and a Vps22–Vps36 subcomplex (which contains only the carboxy-terminal region of Vps36 owing to proteolysis) makes up the second branch. The amino-terminal coiled coil of Vps22, which has been predicted to interact with coiled coils in ESCRT-III subunits, protrudes from the tip of the second branch, as does the flexible linker of Vps36 that leads to its ubiquitin-binding domains. Hurley and co-workers therefore propose that larger oligomers of the three ESCRT complexes might form an ordered scaffold, which prevents ubiquitylated cargo diffusing away from the low-affinity binding sites in these complexes. In addition, they propose that the complexes have “...long swinging arms for the transfer of cargo over distances of tens to hundreds of Å”. This structure-based conceptual framework takes us a step closer to a complete mechanistic understanding of this pathway. REFERENCES Hierro, A. et al. Structure of the ESCRT-II endosomal trafficking complex. Nature 431, 221-225 (2004)

Protected from birth

As they emerge from a ribosomal exit tunnel, newly synthesized proteins are met by chaperones that help them fold into their native state, and the principle of ribosome-associated chaperones has been conserved in prokaryotes and eukaryotes. But how do such chaperones support protein folding? Ban and colleagues now shed light on the matter in Nature.

They describe the 2.7-Å-resolution crystal structure of the most well-characterized ribosome-associated chaperone, trigger factor (TF) from Escherichia coli. In addition, they describe the 3.5-Å-resolution crystal structure of an amino-terminal TF fragment that is bound to the large ribosomal subunit of Haloarcula marismortui. They found that TF adopts a “crouching dragon” shape. The amino-terminal, ribosome-binding domain forms the tail, the carboxy-terminal domain makes up the arms and the back and, together, these domains form an arch. The peptidyl-prolyl isomerase domain, which is not essential for the chaperone activity of TF, forms the head. By combining their structural data, the authors show that TF seems to hunch over the ribosomal exit tunnel, extending the hydrophobic inner face of the arch towards the nascent polypeptide and providing a well-defined, shielded 'cage' for protein folding. This cage is can hold a folded protein domain, and these data have highlighted “...an unexpected mechanism of action for ribosome-associated chaperones”. REFERENCE Ferbitz, L. et al. Trigger factor in complex with the ribosome forms a molecular cradle for nascent proteins. Nature 29 Aug 2004 (doi:10.1038/nature02899)