| Structural highlights
Disease
PALS1_HUMAN Non-specific syndromic intellectual disability.
Function
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][1] [2] [3] [4] (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.[5] [6]
Publication Abstract from PubMed
Many components of epithelial polarity protein complexes possess PDZ domains that are required for protein interaction and recruitment to the apical plasma membrane. Apical localization of the Crumbs (Crb) transmembrane protein requires a PDZ-mediated interaction with Pals1 (protein-associated with Lin7, Stardust, MPP5), a member of the p55 family of membrane-associated guanylate kinases (MAGUKs). This study describes the molecular interaction between the Crb carboxy-terminal motif (ERLI), which is required for Drosophila cell polarity, and the Pals1 PDZ domain using crystallography and fluorescence polarization. Only the last four Crb residues contribute to Pals1 PDZ-domain binding affinity, with specificity contributed by conserved charged interactions. Comparison of the Crb-bound Pals1 PDZ structure with an apo Pals1 structure reveals a key Phe side chain that gates access to the PDZ peptide-binding groove. Removal of this side chain enhances the binding affinity by more than fivefold, suggesting that access of Crb to Pals1 may be regulated by intradomain contacts or by protein-protein interaction.
Structures of the human Pals1 PDZ domain with and without ligand suggest gated access of Crb to the PDZ peptide-binding groove.,Ivanova ME, Fletcher GC, O'Reilly N, Purkiss AG, Thompson BJ, McDonald NQ Acta Crystallogr D Biol Crystallogr. 2015 Mar 1;71(Pt 3):555-64. doi:, 10.1107/S139900471402776X. Epub 2015 Feb 26. PMID:25760605[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ Ivanova ME, Fletcher GC, O'Reilly N, Purkiss AG, Thompson BJ, McDonald NQ. Structures of the human Pals1 PDZ domain with and without ligand suggest gated access of Crb to the PDZ peptide-binding groove. Acta Crystallogr D Biol Crystallogr. 2015 Mar 1;71(Pt 3):555-64. doi:, 10.1107/S139900471402776X. Epub 2015 Feb 26. PMID:25760605 doi:http://dx.doi.org/10.1107/S139900471402776X
|
