SQSTM1 (sequestosome 1)

5q35.3

440 amino acids (aa). SQSTM1 (sequestosome 1), also called p62, is a scaffolding protein with several interaction domains; it is composed of an OPR domain (octatricopeptide repeat (PB1 dimerization domain)), a Zn finger, a LIM protein-binding region, a TRAF6-binding motif, a PEST sequence (proline, glutamic acid, serine, and threonine rich), a LIR motif (LC3 interaction region, SGGDDDWTHLSS), a second PEST sequence, a KIR (keap1 interacting region), and an UBA (ubiquitin-associated) domain. Interacts with Caspase-8 and the apoptosis, machinery, MAPK kinases such as MAP2K5 (15q23), LCK (1p34), NBR1 (17q21), PRKCI (3q26), PAWR (12q21), RIPK1 (6p25), TRAF6 (11p12) and NTRK1 (1q23) and the NF-kappaB pathway, KEAP1 (19p13), GABARAPL1 (12p13), MAP1LC3A/LC3 (20q11), and ubiquitin. Mediates the interaction between TRAF6 and CYLD (16q12). Implicated in the activation of the transcription factor NF-kappaB. Involved in the autophagy-lysosome pathway. Plays a role in the formation of cytoplasmic proteinaceous inclusions in various pathologic situations where autophagy is inactivated (Geetha and Wooten, 2002; Lamark et al., 2009; Moscat and Diaz-Meco, 2009; Moscat et al., 2009; Ichimura and Komatsu, 2010; Komatsu and Ichimura, 2010; Moscat and Diaz-Meco, 2011).

Mutated in Pagets disease of bone.

NUP214 (nucleoporin 214kDa)

9q34.13

The previous name of NUP214 was CAN.

2090 aa; contains dimerization domains (leucine zippers and FG repeats). The NUP214 N-terminal domain (NTD, aa 1-450) is composed of the seven-bladed β-propeller domain (aa 41-405), with, in particular, the 6D7A loop, an inter-blade connector loop that encompasses 20 residues (aa 342-361: LLEDSSRAELPVTDKSDDSL), followed by the 30-residue C-terminal extension (CTE aa 405-434) that binds to the bottom face of the β-propeller, followed by a flexible linker, the coiled-coil domain (aa 680-1209) with two leucine-zippers (aa 740-768 and 861-882), and the C-terminal region with numerous FG-repeats (phenylalanine-glycine repeat motifs, aa 1809-2090). The CTE contains several putative phosphorylation sites, including Ser-430 and Thr-437. Component of the nuclear pore complex involved in nucleo-cytoplasmic transport. NUP214 is localized in the nuclear membrane, on the cytoplasmic face of the nucleopore complex. NUP214, NUP88 and XPO1 form a subcomplex which anchors the cytoplasmic fibrils to the nuclear pore complex.

The N-terminal region of NUP214 is involved in mRNA export: it has been found to interact with the DEAD box helicase DDX19, and mutations in DDX19 that disrupt binding to NUP214 inhibit mRNA export The 6D7A loop of the NUP214 NTD is required for complex formation with DDX19. (Köser et al., 2005; Napetschnig et al., 2007; Napetschnig et al., 2009).