New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental disorder and impairment of the WRC-mediated actin dynamics

Begemann, Anaïs; Sticht, Heinrich; Begtrup, Amber; Vitobello, Antonio; Faivre, Laurence; Banka, Siddharth; Alhaddad, Bader; Asadollahi, Reza; Becker, Jéssica; Bierhals, Tatjana; Brown, Kathleen; Bruel, Ange‐Line; Brunet, Theresa; Carneiro, Maryline; Cremer, Kirsten; Day, Robert C.; Denommé‐Pichon, Anne‐Sophie; Dyment, Dave A; Engels, Hartmut; Fisher, Rachel; Goh, Elaine Suk‐Ying; Hajianpour, M J; Haertel, Lucia Ribeiro Machado; Hauer, Nadine; Hempel, Maja; Herget, Theresia; Johannsen, Jessika; Kraus, Cornelia; Guyader, Gwenaël Le; Lesca, Gaëtan; Mau-Them, Frédéric Tran; McDermott, John H; McWalter, Kirsty; Meyer, Pierre; Õunap, Katrin; Popp, Bernt; Reimand, Tiia; Riedhammer, Korbinian; Russo, Martina; Sadleir, Lynette G.; Saenz, Margarita; Schiff, Manuel; Schüler, Elisabeth; Syrbe, Steffen; Ven, Amelie T. van der; Verloès, Alain; Willems, Marjolaine; Zweier, Christiane; Steindl, Katharina; Zweier, Christiane; Rauch, Anita

doi:10.1038/s41436-020-01011-x

Cited by 36 publications

(52 citation statements)

References 40 publications

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“…Many missense mutations, either identified in Cyfip2 from human patients or previously designed based on the crystal structure (WRC xtal ; PDB: 3P8C) to disrupt WRC autoinhibition, are located in the Tyrosine lock region and the “stem” regions ( Fig. 4D , indicated by red and yellow dots, respectively) 8, 27, 29, 30 . Single point mutation in these regions was typically sufficient to cause disease or autoactivation of WRC, suggesting the interactions in the Tyrosine lock and the “stem” region are highly cooperative 8, 21, 28 .…”

Section: Resultsmentioning

confidence: 99%

“…3A). On the Rac1 side, the interactions involve the end of the a1 helix (a.a. [23][24][25], most of Switch I (a.a. [26][27][28][29][30][31][32][33][34][35][36][37], the b2-b3 betasheet connecting Switch I and Switch II (a.a. [38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55], and the beginning of Switch II (a.a. 56-70) (Fig. 3A,B).…”

Section: Interactions Between Rac1 and The A Site Of Wrcmentioning

confidence: 99%

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Structures reveal a key mechanism of WAVE Regulatory Complex activation by Rac1 GTPase

Ding

Yang

Schaks

et al. 2022

Preprint

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Rho-family GTPase Rac1 activates the WAVE regulatory complex (WRC) to drive Arp2/3-mediated actin polymerization in many essential processes. Rac1 binds to WRC at two distinct sites—the A and D sites. Precisely how Rac1 binds and how the binding triggers WRC activation remain unknown. Here we report WRC structures by itself, and when bound to single or double Rac1 molecules, at ∼3 Å resolutions by cryogenic-electron microscopy. The structures reveal that Rac1 binds to the two sites by distinct mechanisms, and binding to the A site, but not the D site, drives WRC activation. Activation involves a series of unique conformational changes leading to the release of sequestered WCA (WH2- central-acidic) polypeptide, which stimulates the Arp2/3 complex to polymerize actin. Together with biochemical and cellular analyses, the structures provide a novel mechanistic understanding of how the Rac1-WRC-Arp2/3-actin signaling axis is regulated in diverse biological processes and diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Interactions Between Rac1 and The A Site Of Wrcmentioning

confidence: 99%

Structures reveal a key mechanism of WAVE Regulatory Complex activation by Rac1 GTPase

Ding

Yang

Schaks

et al. 2022

Preprint

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“…In humans, CYFIP2 variants have been reported to be linked to ID ( 26 , 27 ). Notably, visual impairment is frequently observed in individuals with ID ( 2 ).…”

Section: Discussionmentioning

confidence: 99%

“…Notably, visual impairment is frequently observed in individuals with ID ( 2 ). Some ID cases harboring CYFIP2 variants exhibit visual impairments ( 26 , 27 ). We found alterations in the retinal ganglion cell properties and impaired OKRs in Cyfip2 CKO mice.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, recent whole-exome and whole-genome sequencing identified CYFIP2 variants in individuals with early-onset epileptic encephalopathy, developmental delay and ID ( 25–27 ). Generally, CYFIP2 variants in individuals with ID are linked to visual impairments ( 26 , 27 ). However, the underlying mechanisms of visual impairment associated with CYFIP2 variants remain unclear.…”

Section: Introductionmentioning

confidence: 99%

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Deficiency of the neurodevelopmental disorder-associated geneCyfip2alters the retinal ganglion cell properties and visual acuity

Chaya

Ishikane

Varner

et al. 2021

Human Molecular Genetics

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Intellectual disability (ID) is a neurodevelopmental disorder affecting approximately 0.5%–3% of the population in the developed world. Individuals with ID exhibit deficits in intelligence, impaired adaptive behavior, and often visual impairments. Cytoplasmic fragile X mental retardation 1 (FMR1)-interacting protein 2 (CYFIP2) is an interacting partner of the FMR protein, whose loss results in fragile X syndrome, the most common inherited cause of ID. Recently, CYFIP2 variants have been found in patients with early-onset epileptic encephalopathy, developmental delay, and ID. Such individuals often exhibit visual impairments; however, the underlying mechanism is poorly understood. In the present study, we investigated the role of Cyfip2 in retinal and visual functions by generating and analyzing Cyfip2 conditional knockout (CKO) mice. While we found no major differences in the layer structures and cell compositions between the control and Cyfip2 CKO retinas, a subset of genes associated with the transporter and channel activities was differentially expressed in Cyfip2 CKO retinas than in the controls. Multi-electrode array recordings showed more sustained and stronger responses to positive flashes of the ON ganglion cells in the Cyfip2 CKO retina than in the controls, although electroretinogram analysis revealed that Cyfip2 deficiency unaffected the photoreceptor and ON bipolar cell functions. Furthermore, initial and late phase optokinetic responses analysis demonstrated that Cyfip2 deficiency impaired the visual function at the organismal level. Together, our results shed light on the molecular mechanism underlying the visual impairments observed in individuals with CYFIP2 variants and more generally, in patients with neurodevelopmental disorders, including ID.

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Computational analysis of protein–protein interactions of cancer drivers in renal cell carcinoma

Pei,

Zhang,

Cong

2023

FEBS Open Bio

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Renal cell carcinoma (RCC) is the most common type of kidney cancer with rising cases in recent years. Extensive research has identified various cancer‐driver proteins associated with different subtypes of RCC. Most RCC drivers are encoded by tumor suppressor genes and exhibit enrichment in functional categories such as protein degradation, chromatin remodeling, and transcription. To further our understanding of RCC, we utilized powerful deep learning methods based on AlphaFold to predict protein‐protein interactions (PPIs) involving RCC drivers. We predicted high‐confidence complexes formed by various RCC drivers, including TCEB1, KMT2C/D, and KDM6A of the COMPASS‐related complexes, TSC1 of the MTOR pathway, and TRRAP. These predictions provide valuable structural insights into the interaction interfaces, some of which are promising targets for cancer drug design, such as the NRF2‐MAFK interface. Cancer somatic missense mutations from large datasets of genome sequencing of RCCs were mapped to the interfaces of predicted and experimental structures of PPIs involving RCC drivers, and their effects on the binding affinity were evaluated. We observed more than 100 cancer somatic mutations affecting the binding affinity of complexes formed by key RCC drivers such as VHL and TCEB1. These findings emphasize the importance of these mutations in RCC pathogenesis and potentially offer new avenues for targeted therapies.

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New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental disorder and impairment of the WRC-mediated actin dynamics

Cited by 36 publications

References 40 publications

Structures reveal a key mechanism of WAVE Regulatory Complex activation by Rac1 GTPase

Structures reveal a key mechanism of WAVE Regulatory Complex activation by Rac1 GTPase

Deficiency of the neurodevelopmental disorder-associated geneCyfip2alters the retinal ganglion cell properties and visual acuity

Computational analysis of protein–protein interactions of cancer drivers in renal cell carcinoma

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