Oligomerized liprin-α promotes phase separation of ELKS for compartmentalization of presynaptic active zone proteins

Liang, Mingfu; Jin, Gaowei; Xie, Xiao‐Bi; Zhang, Wenchao; Li, Kaiyue; Niu, Fujun; Ye, Cong; Wei, Zhiyi

doi:10.1016/j.celrep.2021.109476

Cited by 5 publications

(8 citation statements)

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“…Liprin-α proteins from various species form condensates in cells through a process termed liquid-liquid phase separation (LLPS) (Emperador-Melero et al ., 2021; Liang et al ., 2021; McDonald et al , 2020; Xie et al ., 2021). During LLPS, proteins form dynamic, non-membrane surrounded compartments through demixing from the diffuse state out of the cytosol (Bracha et al , 2019).…”

Section: Resultsmentioning

confidence: 99%

“…Liprin-α proteins have been shown to be early organizers of presynaptic development by recruiting ELKS, RIM and CASK (Dai et al , 2006; Spangler et al , 2013). The ability of Liprin-α proteins to undergo LLPS has now been documented in several studies; LLPS is driven by multimerization of its N-terminal coiled-coil motifs, which leads to a high local concentration of Liprin-α and associated ELKS molecules (Liang et al ., 2021). Furthermore, a central intrinsically disordered region (see Fig.…”

Section: Discussionmentioning

confidence: 99%

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Regulation of Liprin-α phase separation by CASK is disrupted by a mutation in its CaM kinase domain

Tibbe

Ferle

Nampoothiri

et al. 2022

Preprint

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CASK is a unique membrane associated guanylate kinase (MAGUK), due to its Ca2+/calmodulin-dependent kinase (CaMK) domain. We describe four male patients with a severe neurodevelopmental disorder with microcephaly carrying missense variants affecting the CaMK domain. One boy who carried the p.E115K variant and died at an early age showed pontocerebellar hypoplasia (PCH) in addition to microcephaly, thus exhibiting the classical MICPCH phenotype observed in individuals with CASK loss-of-function variants. All four variants selectively weaken the interaction of CASK with Liprin-α2, a component of the presynaptic active zone. Liprin-α proteins form spherical condensates in a process termed liquid-liquid phase separation (LLPS), which we observe here in Liprin-α2 overexpressing HEK293T cells and primary cultured neurons. Condensate formation is reversed by interaction of Liprin-α2 with CASK; this is associated with altered phosphorylation of Liprin-α2. The p.E115K variant fails to interfere with condensate formation. As the individual carrying this variant had the severe MICPCH disorder, we suggest that regulation of Liprin-α2-mediated LLPS is a new functional feature of CASK which must be maintained to prevent PCH.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Regulation of Liprin-α phase separation by CASK is disrupted by a mutation in its CaM kinase domain

Tibbe

Ferle

Nampoothiri

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Liprin-α proteins have been shown to be early organizers of presynaptic development by recruiting ELKS, RIM, and CASK (Dai et al, 2006;Spangler et al, 2013). The ability of Liprin-α proteins to undergo LLPS has now been documented in several studies; LLPS is driven by multimerization of its N-terminal coiled-coil motifs, which leads to a high local concentration of Liprin-α and associated ELKS molecules (Liang et al, 2021). Furthermore, a central IDR (see Fig 5C ) in Liprin-α proteins from different species contributes to LLPS 293T cells expressing Liprin-α2 alone or in combination with CASK-WT were lysed, and HA-tagged Liprin was immunoprecipitated using anti-HA magnetic beads.…”

Section: Discussionmentioning

confidence: 99%

“…Liprin-α proteins from various species form condensates in cells through a process termed LLPS (McDonald et al, 2020;Emperador-Melero et al, 2021;Liang et al, 2021;Xie et al, 2021). During LLPS, proteins form dynamic, non-membrane surrounded compartments through demixing from the diffuse state out of the cytosol (Bracha (A) Protein domains of CASK, selected interaction partners, and missense variants in the CASK gene identified here.…”

Section: All Cask Variants Exhibit Reduced Binding To Liprin-α2mentioning

confidence: 96%

“…The active zone complex is held together through multiple interactions via highly conserved domains such as C 2 , PDZ, and SH3 domains (Sudhof, 2012). Recently, it became clear that active-zone assembly also relies on a process termed liquid-liquid phase separation (LLPS), which involves the recruitment of proteins into condensates mediated by multiple intrinsically disordered regions (IDRs) (Emperador-Melero et al, 2021;Liang et al, 2021;Xie et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

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Regulation of Liprin-α phase separation by CASK is disrupted by a mutation in its CaM kinase domain

et al. 2022

View full text Add to dashboard Cite

CASK is a unique membrane-associated guanylate kinase (MAGUK) because of its Ca2+/calmodulin-dependent kinase (CaMK) domain. We describe four male patients with a severe neurodevelopmental disorder with microcephaly carrying missense variants affecting the CaMK domain. One boy who carried the p.E115K variant and died at an early age showed pontocerebellar hypoplasia (PCH) in addition to microcephaly, thus exhibiting the classical MICPCH phenotype observed in individuals with CASK loss-of-function variants. All four variants selectively weaken the interaction of CASK with Liprin-α2, a component of the presynaptic active zone. Liprin-α proteins form spherical phase-separated condensates, which we observe here in Liprin-α2 overexpressing HEK293T cells. Large Liprin-α2 clusters were also observed in transfected primary-cultured neurons. Cluster formation of Liprin-α2 is reversed in the presence of CASK; this is associated with altered phosphorylation of Liprin-α2. The p.E115K variant fails to interfere with condensate formation. As the individual carrying this variant had the severe MICPCH disorder, we suggest that regulation of Liprin-α2–mediated phase condensate formation is a new functional feature of CASK which must be maintained to prevent PCH.

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Specific multivalent molecules boost CRISPR-mediated transcriptional activation

Chen,

Shi,

Yao

et al. 2024

Nat Commun

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Oligomerized liprin-α promotes phase separation of ELKS for compartmentalization of presynaptic active zone proteins

Cited by 5 publications

References 0 publications

Regulation of Liprin-α phase separation by CASK is disrupted by a mutation in its CaM kinase domain

Regulation of Liprin-α phase separation by CASK is disrupted by a mutation in its CaM kinase domain

Regulation of Liprin-α phase separation by CASK is disrupted by a mutation in its CaM kinase domain

Specific multivalent molecules boost CRISPR-mediated transcriptional activation

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