MAGUKs end a tale of promiscuity

Reißner, Carsten; Missler, Markus

doi:10.1073/pnas.1420387111

Cited by 6 publications

(4 citation statements)

References 18 publications

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“…Work from other groups supports the idea that in MAGUK proteins, the PDZ, SH3 and GuK domains form a supramodule stabilized by inter-domain interactions predominantly between the PDZ and SH3 domains (Li et al 2014; Reissner and Missler 2014); (Pan et al 2011; Zeng et al 2017). In PALS1, the structure of this module is critical for a high-affinity interaction with a protein binding partner via the PDZ motif, and any disruption of the supramodule weakens this protein-protein interaction.…”

Section: Resultsmentioning

confidence: 79%

“…The CASK-neurexin interaction is evolutionarily conserved and purportedly occurs through the PDZ domain (Hata et al 1996; LaConte et al 2014). Experimentally, however, a large portion of CASK, including the SH3-GuK domain, is necessary for this interaction, indicating that neurexin interacts with CASK via multiple domains (Hata et al 1996; Li et al 2014; Reissner and Missler 2014). In fact for both neurexin and syndecan, additional secondary sites of interaction have been hypothesized (Daniels et al 1998).…”

Section: Discussionmentioning

confidence: 99%

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Two microcephaly-associated novel missense mutations in CASK specifically disrupt the CASK–neurexin interaction

et al. 2018

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Deletion and truncation mutations in the X-linked gene CASK are associated with severe intellectual disability (ID), microcephaly and pontine and cerebellar hypoplasia in girls (MICPCH). The molecular origin of CASK-linked MICPCH is presumed to be due to disruption of the CASK-Tbr-1 interaction. This hypothesis, however, has not been directly tested. Missense variants in CASK are typically asymptomatic in girls. We report three severely affected girls with heterozygous CASK missense mutations (M519T (2), G659D (1)) who exhibit ID, microcephaly, and hindbrain hypoplasia. The mutation M519T results in the replacement of an evolutionarily invariant methionine located in the PDZ signaling domain known to be critical for the CASK-neurexin interaction. CASK is incapable of binding to neurexin, suggesting a critically important role for the CASK-neurexin interaction. The mutation G659D is in the SH3 (Src homology 3) domain of CASK, replacing a semi-conserved glycine with aspartate. We demonstrate that the CASK mutation affects the CASK protein in two independent ways: (1) it increases the protein's propensity to aggregate; and (2) it disrupts the interface between CASK's PDZ (PSD95, Dlg, ZO-1) and SH3 domains, inhibiting the CASK-neurexin interaction despite residing outside of the domain deemed critical for neurexin interaction. Since heterozygosity of other aggregation-inducing mutations (e.g., CASK) does not produce MICPCH, we suggest that the G659D mutation produces microcephaly by disrupting the CASK-neurexin interaction. Our results suggest that disruption of the CASK-neurexin interaction, not the CASK-Tbr-1 interaction, produces microcephaly and cerebellar hypoplasia. These findings underscore the importance of functional validation for variant classification.

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Section: Resultsmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Two microcephaly-associated novel missense mutations in CASK specifically disrupt the CASK–neurexin interaction

et al. 2018

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“…The CASK-neurexin interaction was traditionally suggested to be mediated by the binding of a few residues at the end of neurexin’s cytoplasmic tail to CASK’s PDZ domain ( LaConte et al, 2016 ; LaConte et al, 2018 ), and missense variants located on the PDZ domain may be linked to developmental disorders with/without microcephaly ( Seto et al, 2017 ). However, other studies show that additional domains, such as the SH3-Guk domain, are necessary for the interaction ( Li et al, 2014 ; Reissner and Missler, 2014 ). A PDZ-mediated connection can be broken by variants in the SH3 domain, which can also cause protein aggregation ( LaConte et al, 2018 ; Kerr et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Case Report: Identification of a novel CASK missense variant in a Chinese family with MICPCH

Zhang

Jia

Yao³

et al. 2022

Front. Genet.

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Mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH) is a rare genetic disorder that results in varying levels of pontocerebellar hypoplasia, microcephaly, and severe intellectual disabilities. Prior genetic analyses have identified the CASK gene as a driver of MICPCH. Herein, we analyzed a Chinese family with MICPCH. The index patient was an 8-year-old male. He and his 3-year-old brother suffered from microcephaly, pontocerebellar hypoplasia, serious mental retardation, ataxia, gait disorder, and inability to speak. Through a combination of whole-exome sequencing and subsequent Sanger sequencing, a novel X-linked missense mutation, c.1882G>C (p.D628H) in the CASK gene, was identified in two siblings, as well as their mother and grandmother, who exhibited mild mental retardation. Other family members with negative genetic testing were normal. In silico analyses indicated that this missense mutation was predicted to reduce CASK protein stability, disrupt the SRC homology 3 (SH3) domain, and abolish its function. In summary, we identified a novel missense variate in CASK associated with MICPCH. Our work facilitates the diagnosis of the disease in this family and broadens the gene variant spectrum of the CASK in MICPCH patients.

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“…Without ligand the protein is elongated (left in Fig 9B ), whereas binding of a ligand induces reorganization of the domains to a U-shape [ 42 ]. The required flexibility for this conformational change is provided by a hinge or linker region [ 10 , 45 ]. The splice inserts encoded by exon 19, 20 and 23L are located between the PDZ and SH3 domain (exon 19 and 20) and at the beginning of the so-called hook region in between the SH3 and GK domain (exon 23L; see central model in Fig 9B ), thus inside the PSG tandem module.…”

Section: Discussionmentioning

confidence: 99%

Functional analysis of CASK transcript variants expressed in human brain

et al. 2021

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The calcium-/calmodulin dependent serine protein kinase (CASK) belongs to the membrane-associated guanylate kinases (MAGUK) family of proteins. It fulfils several different cellular functions, ranging from acting as a scaffold protein to transcription control, as well as regulation of receptor sorting. CASK functions depend on the interaction with a variety of partners, for example neurexin, liprin-α, Tbr1 and SAP97. So far, it is uncertain how these seemingly unrelated interactions and resulting functions of CASK are regulated. Here, we show that alternative splicing of CASK can guide the binding affinity of CASK isoforms to distinct interaction partners. We report seven different variants of CASK expressed in the fetal human brain. Four out of these variants are not present in the NCBI GenBank database as known human variants. Functional analyses showed that alternative splicing affected the affinities of CASK variants for several of the tested interaction partners. Thus, we observed a clear correlation of the presence of one splice insert with poor binding of CASK to SAP97, supported by molecular modelling. The alternative splicing and distinct properties of CASK variants in terms of protein-protein interaction should be taken into consideration for future studies.

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MAGUKs end a tale of promiscuity

Cited by 6 publications

References 18 publications

Two microcephaly-associated novel missense mutations in CASK specifically disrupt the CASK–neurexin interaction

Two microcephaly-associated novel missense mutations in CASK specifically disrupt the CASK–neurexin interaction

Case Report: Identification of a novel CASK missense variant in a Chinese family with MICPCH

Functional analysis of CASK transcript variants expressed in human brain

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