Lamina Associated Polypeptide 1 (LAP1) Interactome and Its Functional Features

Abstract

Lamina-associated polypeptide 1 (LAP1) is a type II transmembrane protein of the inner nuclear membrane encoded by the human gene TOR1AIP1. LAP1 is involved in maintaining the nuclear envelope structure and appears be involved in the positioning of lamins and chromatin. To date, LAP1’s precise function has not been fully elucidated but analysis of its interacting proteins will permit unraveling putative associations to specific cellular pathways and cellular processes. By assessing public databases it was possible to identify the LAP1 interactome, and this was curated. In total, 41 interactions were identified. Several functionally relevant proteins, such as TRF2, TERF2IP, RIF1, ATM, MAD2L1 and MAD2L1BP were identified and these support the putative functions proposed for LAP1. Furthermore, by making use of the Ingenuity Pathways Analysis tool and submitting the LAP1 interactors, the top two canonical pathways were “Telomerase signalling” and “Telomere Extension by Telomerase” and the top functions “Cell Morphology”, “Cellular Assembly and Organization” and “DNA Replication, Recombination, and Repair”. Once again, putative LAP1 functions are reinforced but novel functions are emerging.

Nuclear envelope dysfunction and its contribution to the aging process

“…The INM protein lamina‐associated polypeptide 1 (LAP1) is also involved in lamins and chromatin positioning, and it was recently associated with telomeres function by TRF2 and RIF1 binding. However, the molecular mechanism through which LAP1 and TRF2 regulate telomere function remains to be elucidated (Serrano, Cruz e Silva, & Rebelo, 2016).…”

DYT1 dystonia patient-derived fibroblasts have increased deformability and susceptibility to damage by mechanical forces

“…264 265We next investigated the effects of A-type lamins on cell filtration, as they are established regulators 266 of cellular mechanotype(Lammerding et al, 2004;Swift et al, 2013) and directly interact with 267 DYT1 dystonia patient-derived fibroblasts have increased deformability and susceptibility to damage by mechanical forces 7 LAP1(Foisner and Gerace, 1993;Serrano et al, 2016) and SUN1/2(Chang et al, 2015b). We found 268 that MEFs isolated from lamin A/C-knock-out (LMNA -/-) mice exhibited a reduced % retention 269 relative to MEFs isolated from control mice (LMNA +/+ ) (Figure 2C).The increased deformability of 270 the LMNA -/-MEFs that we observed is consistent with previous studies from our laboratory and 271 others, which show that A-type lamins determine the ability of cells to deform through micron-scale 272 pores, both during passive deformation driven by applied pressure (timescale ~ seconds) and active 273 migration (timescale ~ hours) (Rowat et al, 2013; Denais et al, 2016; Irianto et al, 2017).…”

Two novel cases further expand the phenotype of TOR1AIP1-associated nuclear envelopathies

“…Given the role of LAP1B in the maintenance of nuclear membrane morphology (Kim et al 2010;Serrano et al 2016) and previous findings in individuals affected by a TOR1AIP1-associated disorder (Fichtman et al 2019;Kayman-Kurekci et al 2014), we performed immunofluorescence analysis of fibroblasts derived from individual 1 and an unaffected control individual. In control fibroblasts, all cells displayed positive lamin A/C staining, and the majority, around 90%, of nuclei were oval or ovoid (Fig.…”