The self-association and activity regulation of LRSAM1 E3 ligase

Bian, Weixiang; Guo, Yanmin; Zhang, Yuan; Li, Hongtao

doi:10.1016/j.bbrc.2017.02.026

Cited by 7 publications

(7 citation statements)

References 26 publications

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“…Fourth, WT Rapsn was able to rescue AChR clustering deficits in N88K mt mice; this rescue effect was not observed with Y86F mt Rapsn. Finally, we demonstrate that N88 and Y86 are both necessary for Rapsn self-association, a process that has been shown to be necessary for E3 ligase activation (Bian et al, 2017; Ho et al, 2015; Koliopoulos et al, 2016; Liew et al, 2010; Metzger et al, 2014; Nikolay et al, 2004; ). A parsimonious explanation of these results is that MuSK activation causes, directly or indirectly, Rapsn tyrosine phosphorylation at Y86, which promotes Rapsn self-association and thus activate the E3 ligase activity, revealing a mechanism for Rapsn activation.…”

Section: Discussionmentioning

confidence: 67%

“…Next, we investigated how Y86F mutation impairs E3 ligase activity of Rapsn. E3 ligases including those containing RING-domain are regulated by self-association (Bian et al, 2017; Ho et al, 2015; Koliopoulos et al, 2016; Liew et al, 2010; Metzger et al, 2014; ; Nikolay et al, 2004). The TPR domains in the N-terminus of Rapsn are thought to mediate self-association and thus form aggregates in heterologous cells (Maimone and Merlie, 1993; Ramarao et al, 2001).…”

Section: Resultsmentioning

confidence: 99%

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A mechanism in agrin signaling revealed by a prevalent Rapsyn mutation in congenital myasthenic syndrome

Xing

Jing

Zhang

et al. 2019

eLife

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Neuromuscular junction is a synapse between motoneurons and skeletal muscles, where acetylcholine receptors (AChRs) are concentrated to control muscle contraction. Studies of this synapse have contributed to our understanding of synapse assembly and pathological mechanisms of neuromuscular disorders. Nevertheless, underlying mechanisms of NMJ formation was not well understood. To this end, we took a novel approach – studying mutant genes implicated in congenital myasthenic syndrome (CMS). We showed that knock-in mice carrying N88K, a prevalent CMS mutation of Rapsyn (Rapsn), died soon after birth with profound NMJ deficits. Rapsn is an adapter protein that bridges AChRs to the cytoskeleton and possesses E3 ligase activity. In investigating how N88K impairs the NMJ, we uncovered a novel signaling pathway by which Agrin-LRP4-MuSK induces tyrosine phosphorylation of Rapsn, which is required for its self-association and E3 ligase activity. Our results also provide insight into pathological mechanisms of CMS.

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Section: Discussionmentioning

confidence: 67%

Section: Resultsmentioning

confidence: 99%

A mechanism in agrin signaling revealed by a prevalent Rapsyn mutation in congenital myasthenic syndrome

Xing

Jing

Zhang

et al. 2019

eLife

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“…LRASM1, E3 ubiquitin-protein ligase recognize and ubiquitinate various bacteria by initiating the autophagic reaction. This reflects that, LRSAM may play an imperative role in resistance to cellular bacteria by autophagy [ 21 , 22 ]. A recent finding indicates that the level of LRSAM1 is significantly up-regulated in patients with colorectal cancer, implying that the aberrant expression of LRSAM1 may be involved in the cancer progression [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

Comparative Proteomic Profiling of Tumor-Associated Proteins in Human Gastric Cancer Cells Treated with Pectolinarigenin

Lee

Kim

et al. 2018

Nutrients

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Pectolinarigenin (PEC), a natural flavonoid that is present in citrus fruits, has been reported to exhibit antitumor effects in several cancers. Though the mechanism of PEC-induced cytotoxicity effects has been documented, the proteomic changes that are associated with the cellular response to this flavonoid are poorly understood in gastric cancer cells. In this study, a comparative proteomic analysis was performed to identify proteins associated with PEC-induced cell death in two human gastric cancer cell lines: AGS and MKN-28. Two-dimensional gel electrophoresis (2-DE) revealed a total of 29 and 56 protein spots with significant alteration were screened in AGS and MKN-28 cells respectively. In total, 13 (AGS) and 39 (MKN28) proteins were successfully identified by mass spectrometry from the differential spots and they are known to be involved in signal transduction, apoptosis, transcription and translation, cell structural organization, and metabolism, as is consistent with multiple effects of PEC on tumor cells. Notably, novel target proteins like Probable ATP-dependent RNA helicase DDX4 (DDX4) and E3 ubiquitin-protein ligase LRSAM1 (LRSAM1) along with the commonly differential expressed proteins on both the cell lines that are treated with PEC were confirmed by immunoblotting. The DDX4 accelerates cell cycle progression by abrogating the G2 checkpoint when overexpressed in cancer cells, while the aberrant expression of LRSAM1 may be involved in the cancer pathology. Thus, proteomic analysis provides vital information about target proteins that are important for PEC-induced cell death in gastric cancer cells.

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“…This self-association is critical to the auto-ubiquitination activity that is one of the auto-regulatory mechanisms of the E3 ligases [27]. While the RING domain is pivotal in the ubiquitin transfer, the dimerization is regulated by the CC 1 (coiled-coil-1) and LRR (leucine-rich repeats) domains [30]. The sterile alpha motif (SAM), and PTAP (Pro-Thr/Ser-Ala-Pro) and the second coiled-coil (CC 2 ) domains are responsible for substrate interaction and were observed to impact the ubiquitylation function in vitro [30,31].…”

Section: Lrsam1 Structurementioning

confidence: 99%

LRSAM1 and the RING domain: Charcot–Marie–Tooth disease and beyond

Palaima

Berciano

Peeters

et al. 2021

Orphanet J Rare Dis

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In the past decade, mutations in LRSAM1 were identified as the genetic cause of both dominant and recessive forms of axonal CMT type 2P (CMT2P). Despite demonstrating different inheritance patterns, dominant CMT2P is usually characterized by relatively mild, slowly progressive axonal neuropathy, mainly involving lower limbs, with age of onset between the second and fifth decades of life. Asymptomatic individuals were identified in several pedigrees exemplifying the strong phenotypic variability of these patients requiring serial clinical evaluation to establish correct diagnosis; in this respect, magnetic resonance imaging of lower-limb musculature showing fatty atrophy might be helpful in detecting subclinical gene mutation carriers. LRSAM1 is a universally expressed RING-type E3 ubiquitin protein ligase catalysing the final step in the ubiquitination cascade. Strikingly, TSG101 remains the only known ubiquitination target hampering our mechanistic understanding of the role of LRSAM1 in the cell. The recessive CMT mutations lead to complete loss of LRSAM1, contrary to the heterozygous dominant variants. These tightly cluster in the C-terminal RING domain highlighting its importance in governing the CMT disease. The domain is crucial for the ubiquitination function of LRSAM1 and CMT mutations disrupt its function, however it remains unknown how this leads to the peripheral neuropathy. Additionally, recent studies have linked LRSAM1 with other neurodegenerative diseases of peripheral and central nervous systems. In this review we share our experience with the challenging clinical diagnosis of CMT2P and summarize the mechanistic insights about the LRSAM1 dysfunction that might be helpful for the neurodegenerative field at large.

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The self-association and activity regulation of LRSAM1 E3 ligase

Cited by 7 publications

References 26 publications

A mechanism in agrin signaling revealed by a prevalent Rapsyn mutation in congenital myasthenic syndrome

A mechanism in agrin signaling revealed by a prevalent Rapsyn mutation in congenital myasthenic syndrome

Comparative Proteomic Profiling of Tumor-Associated Proteins in Human Gastric Cancer Cells Treated with Pectolinarigenin

LRSAM1 and the RING domain: Charcot–Marie–Tooth disease and beyond

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