3uit

Structural highlights

Disease

PALS1_HUMAN Non-specific syndromic intellectual disability.

Function

LIN7B_MOUSE Plays a role in establishing and maintaining the asymmetric distribution of channels and receptors at the plasma membrane of polarized cells. Forms membrane-associated multiprotein complexes that may regulate delivery and recycling of proteins to the correct membrane domains. The tripartite complex composed of LIN7 (LIN7A, LIN7B or LIN7C), CASK and APBA1 may have the potential to couple synaptic vesicle exocytosis to cell adhesion in brain. Ensures the proper localization of GRIN2B (subunit 2B of the NMDA receptor) to neuronal postsynaptic density and may function in localizing synaptic vesicles at synapses where it is recruited by beta-catenin and cadherin. Required to localize Kir2 channels, GABA transporter (SLC6A12) and EGFR/ERBB1, ERBB2, ERBB3 and ERBB4 to the basolateral membrane of epithelial cells. May increase the amplitude of ASIC3 acid-evoked currents by stabilizing the channel at the cell surface.^[1] INADL_RAT Scaffolding protein that facilitates the localization of proteins to the cell membrane (By similarity). Required for the correct formation of tight junctions and epithelial apico-basal polarity (By similarity). Positively regulates epithelial cell microtubule elongation and cell migration, possibly via facilitating localization of PRKCI/aPKC and PAR3D/PAR3 at the leading edge of migrating cells (By similarity). Plays a role in the correct reorientation of the microtubule-organizing center during epithelial migration (By similarity). May regulate the surface expression and/or function of ASIC3 in sensory neurons (By similarity). May recruit ARHGEF18 to apical cell-cell boundaries (By similarity).[UniProtKB:E2QYC9][UniProtKB:Q63ZW7][UniProtKB:Q8NI35]PALS1_HUMAN Plays a role in tight junction biogenesis and in the establishment of cell polarity in epithelial cells (PubMed:16678097, PubMed:25385611). Also involved in adherens junction biogenesis by ensuring correct localization of the exocyst complex protein EXOC4/SEC8 which allows trafficking of adherens junction structural component CDH1 to the cell surface (By similarity). Plays a role through its interaction with CDH5 in vascular lumen formation and endothelial membrane polarity (PubMed:27466317). Required during embryonic and postnatal retinal development (By similarity). Required for the maintenance of cerebellar progenitor cells in an undifferentiated proliferative state, preventing premature differentiation, and is required for cerebellar histogenesis, fissure formation, cerebellar layer organization and cortical development (By similarity). Plays a role in neuronal progenitor cell survival, potentially via promotion of mTOR signaling (By similarity). Plays a role in the radial and longitudinal extension of the myelin sheath in Schwann cells (By similarity). May modulate SC6A1/GAT1-mediated GABA uptake by stabilizing the transporter (By similarity). Plays a role in the T-cell receptor-mediated activation of NF-kappa-B (PubMed:21479189). Required for localization of EZR to the apical membrane of parietal cells and may play a role in the dynamic remodeling of the apical cytoskeleton (By similarity). Required for the normal polarized localization of the vesicular marker STX4 (By similarity). Required for the correct trafficking of the myelin proteins PMP22 and MAG (By similarity). Involved in promoting phosphorylation and cytoplasmic retention of transcriptional coactivators YAP1 and WWTR1/TAZ which leads to suppression of TGFB1-dependent transcription of target genes such as CCN2/CTGF, SERPINE1/PAI1, SNAI1/SNAIL1 and SMAD7 (By similarity).[UniProtKB:B4F7E7][UniProtKB:Q9JLB2]^{[2] [3] [4] [5]} (Microbial infection) Acts as an interaction partner for human coronaviruses SARS-CoV and, probably, SARS-CoV-2 envelope protein E which results in delayed formation of tight junctions and disregulation of cell polarity.^{[6] [7]}

References

1. ↑ Hruska-Hageman AM, Benson CJ, Leonard AS, Price MP, Welsh MJ. PSD-95 and Lin-7b interact with acid-sensing ion channel-3 and have opposite effects on H+- gated current. J Biol Chem. 2004 Nov 5;279(45):46962-8. Epub 2004 Aug 17. PMID:15317815 doi:10.1074/jbc.M405874200
2. ↑ Wells CD, Fawcett JP, Traweger A, Yamanaka Y, Goudreault M, Elder K, Kulkarni S, Gish G, Virag C, Lim C, Colwill K, Starostine A, Metalnikov P, Pawson T. A Rich1/Amot complex regulates the Cdc42 GTPase and apical-polarity proteins in epithelial cells. Cell. 2006 May 5;125(3):535-48. doi: 10.1016/j.cell.2006.02.045. PMID:16678097 doi:http://dx.doi.org/10.1016/j.cell.2006.02.045
3. ↑ Carvalho G, Poalas K, Demian C, Hatchi E, Vazquez A, Bidère N. Participation of the cell polarity protein PALS1 to T-cell receptor-mediated NF-κB activation. PLoS One. 2011 Mar 30;6(3):e18159. PMID:21479189 doi:10.1371/journal.pone.0018159
4. ↑ Li Y, Wei Z, Yan Y, Wan Q, Du Q, Zhang M. Structure of Crumbs tail in complex with the PALS1 PDZ-SH3-GK tandem reveals a highly specific assembly mechanism for the apical Crumbs complex. Proc Natl Acad Sci U S A. 2014 Nov 10. pii: 201416515. PMID:25385611 doi:http://dx.doi.org/10.1073/pnas.1416515111
5. ↑ Brinkmann BF, Steinbacher T, Hartmann C, Kummer D, Pajonczyk D, Mirzapourshafiyi F, Nakayama M, Weide T, Gerke V, Ebnet K. VE-cadherin interacts with cell polarity protein Pals1 to regulate vascular lumen formation. Mol Biol Cell. 2016 Sep 15;27(18):2811-21. PMID:27466317 doi:10.1091/mbc.E16-02-0127
6. ↑ Teoh KT, Siu YL, Chan WL, Schlüter MA, Liu CJ, Peiris JS, Bruzzone R, Margolis B, Nal B. The SARS coronavirus E protein interacts with PALS1 and alters tight junction formation and epithelial morphogenesis. Mol Biol Cell. 2010 Nov 15;21(22):3838-52. PMID:20861307 doi:10.1091/mbc.E10-04-0338
7. ↑ De Maio F, Lo Cascio E, Babini G, Sali M, Della Longa S, Tilocca B, Roncada P, Arcovito A, Sanguinetti M, Scambia G, Urbani A. Improved binding of SARS-CoV-2 Envelope protein to tight junction-associated PALS1 could play a key role in COVID-19 pathogenesis. Microbes Infect. 2020 Nov-Dec;22(10):592-597. PMID:32891874 doi:10.1016/j.micinf.2020.08.006