Nuclear pore complex protein Nup98-Nup96-like, autopeptidase S59 domain superfamily (Nup98_auto-Pept-S59_dom_sf)
Type: Homologous_superfamily

Nuclear pore complexes (NPCs) facilitate all nucleocytoplasmic transport in eukaryotic cells, playing essential roles in cellular homeostasis. The NPC is a modular structure composed of multiple copies of ~30 proteins (nucleoporins, Nups) arranged into distinct subcomplexes . A number of these peptides are synthesised as precursors and undergo self-catalysed cleavage. The largest NPC sub-complex is the heptameric Y-shaped mammalian Nup107-Nup160 complex (called Nup84 complex in budding yeast), an essential scaffolding component of the NPC .

Nup98 and Nup96 are encoded by the same gene that produces a 190 kDa polyprotein with autoproteolytic activity which generates the N-terminal NUP98 and C-terminal NUP96 proteins, part of the Nup107-Nup160 subcomplex . The yeast homologue Nup145 undergoes the similar proteolytic event to produce Nup145N and Nup145C, which are part of the Nup84 complex. The function of the heptamer is to coat the curvature of the nuclear pore complex between the inner and outer nuclear membranes. Nup96, which is predicted to be an α helical solenoid, complexes with Sec13 in the middle of the heptamer. The interaction between Nup96 and Sec13 is the point of curvature in the heptameric complex .

The proteolytic cleavage site of yeast Nup145p has been mapped upstream of an evolutionary conserved serine residue. Then, Nup145C form the heptameric Y-complex together with six other proteins while Nup145N shuttle between the NPC and the nuclear interior. .

Nup98, a component of the nuclear pore that plays its primary role in the export of RNAs, is expressed in two forms, derived from alternate mRNA splicing. Both forms are processed into two peptides through autoproteolysis mediated by the C-terminal domain of hNup98. The three-dimensional structure of the C-terminal domain reveals a novel protein fold, and thus a new class of autocatalytic proteases. The structure further reveals that the suggested nucleoporin RNA binding motif is unlikely to bind to RNA .

The following nucleoporins share an ~150-residue C-terminal domain responsible for NPC targeting :

Vertebrate Nup98, a component of the nuclear pore that plays its primary role in the export of RNAs.

Yeast Nup100, plays an important role in several nuclear export and import pathways including poly(A)+ RNA and protein transport.

Yeast Nup116, involved in mRNA export and protein transport.

Yeast Nup145, involved in nuclear poly(A)+ RNA and tRNA export.

The NUP C-terminal domains of Nup98 and Nup145 possess peptidase S59 autoproteolytic activity. The autoproteolytic sites of Nup98 and Nup145 each occur immediately C-terminal to the NUP C-terminal domain. Thus, although this domain occurs in the middle of each precursor polypeptide, it winds up at the C-terminal end of the N-terminal cleavage product. Cleavage of the peptide chains are necessary for the proper targeting to the nuclear pore .

The NUP C-terminal domain adopts a predominantly β-strand structure. The molecule consists of a six-stranded β-sheet sandwiched against a two-stranded β-sheet and flanked by α-helical regions. The N-terminal helical region consists of two short helices, whereas the stretch on the opposite side of molecule consists of a single, longer helix .