Cryo-EM structure of human Nup155 reveals the biochemical basis for atrial fibrillation linked genetic mutation R391H

Abstract

Human nuclear pore complexes are composed of [~]32 distinct nucleoporins to facilitate bidirectional nucleo-cytoplasmic transport. Many of them have been associated with various human diseases such as an inherited mutation (R391H) in Nup155 is shown as the clinical cause of atrial fibrillation and sudden cardiac arrest. Due to the lack of structural knowledge and mechanistic insights, the roles of Nups in NPC assembly and relevance in human diseases are very restricted. Here, we show the cryo-EM structure of human Nup155 at 5.2-5.7. [A] resolution deciphered from 3 distinct particle classes: N-terminus (19-863), C-terminus (864-1337), and longer N-terminus (19-1069). It revealed intrinsic plasticity at the middle domain of Nup155 and the role of species-specific loop regions in an atypical 7-bladed {beta}-propeller domain to provide a distinct interface for Nup93 and Nup35. Due to the proximity of these Nups interacting sites near the Arginine-391 position, atrial fibrillation linked genetic mutation (R391H) causes dissociation from NPC in absence of N-terminal 112 residues. HighlightsO_LICryo-EM structure of human Nup155 at 5.2 [A] resolution C_LIO_LISeven bladed {beta}-propeller domain at N-terminus of Nup155 exhibited distinct features for interaction with Nup35 and Nup93 C_LIO_LIThe middle domain of Nup155 is highly dynamic in nature C_LIO_LIStructural mapping allows mechanistic interpretation of AF linked R391H mutation C_LI