Crystal structure and functional implication of the RUN domain of human NESCA

Sun, Qinjun; Han, Chuanhui; Liu, Lan; Wang, Yizhi; Deng, Hongyu; Bai, Lin; Jiang, Tao

doi:10.1007/s13238-012-2052-3

Cited by 7 publications

(11 citation statements)

References 30 publications

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“…There are four RUN domains for which crystal structures have been reported: the RUN domain of Rap2-interacting protein x (RPIPx), which is a specific effector of Rap2 (Kukimoto-Niino et al, 2006), the RUN1 and subsequent PLAT domains of Rab6-interacting protein 1 (Rab6IP1) in complex with Rab6 (Recacha et al, 2009), the RUN domain of a new signalling adapter protein in the NGF pathway containing an SH3 domain at the carboxyl-terminus (NESCA; Sun et al, 2012) domain-containing protein 2 (RUSC2) in complex with Rab35 (Lin et al, 2019). The sequence identities among the RUN domains of FYCO1, RPIPx and Rab6IP1 were 13-21%; only NESCA and RUSC2 had a high sequence identity of 51%.…”

Section: Structural Comparison Of Run Domainsmentioning

confidence: 99%

Crystal structure of the FYCO1 RUN domain suggests possible interfaces with small GTPases

2020

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FYCO1 is a multidomain adaptor protein that plays an important role in autophagy by mediating the kinesin-dependent microtubule plus-end-directed transport of autophagosomes. FYCO1 contains a RUN domain, which is hypothesized to function as a specific effector for members of the Ras superfamily of small GTPases, but its role has not been well characterized and its interaction partner(s) have not been identified. Here, the crystal structure of the FYCO1 RUN domain was determined at 1.3 Å resolution. The overall structure of the FYCO1 RUN domain was similar to those of previously reported RUN domains. Detailed structural comparisons with other RUN domains and docking studies suggested a possible interaction interface of the FYCO1 RUN domain with small GTPases of the Ras superfamily.

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Section: Structural Comparison Of Run Domainsmentioning

confidence: 99%

Crystal structure of the FYCO1 RUN domain suggests possible interfaces with small GTPases

2020

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“…NESCA, a signaling adapter protein in the NGF-mediated signaling pathway, contains a RUN domain at the N -terminus [12]. The RUN domain of NESCA comprises nine helices, resembling the other RUN domain-containing proteins [15]. Mutational analyses have demonstrated that the RUN domain is an important structural determinant for the nuclear translocation of NESCA and that the nuclear redistribution of NESCA is essential to its neurite outgrowth-promoting properties [12].…”

Section: Run Domain Binds Several Signaling Moleculesmentioning

confidence: 99%

“…Mutational analyses have demonstrated that the RUN domain is an important structural determinant for the nuclear translocation of NESCA and that the nuclear redistribution of NESCA is essential to its neurite outgrowth-promoting properties [12]. However, the RUN domain of NESCA has different surface electrostatic distributions at the putative GTPase-interacting interface compared to the other RUN domains [15]. The RUN domain of NESCA can bind H-Ras, a downstream signaling molecule of TrkA, as well as TrkA itself, suggesting that the NESCA participates in the NGF-TrkA signaling pathway [15].…”

Section: Run Domain Binds Several Signaling Moleculesmentioning

confidence: 99%

“…However, the RUN domain of NESCA has different surface electrostatic distributions at the putative GTPase-interacting interface compared to the other RUN domains [15]. The RUN domain of NESCA can bind H-Ras, a downstream signaling molecule of TrkA, as well as TrkA itself, suggesting that the NESCA participates in the NGF-TrkA signaling pathway [15]. …”

Section: Run Domain Binds Several Signaling Moleculesmentioning

confidence: 99%

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RUFY, Rab and Rap Family Proteins Involved in a Regulation of Cell Polarity and Membrane Trafficking

Matsuda

2013

IJMS

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Cell survival, homeostasis and cell polarity rely on the control of membrane trafficking pathways. The RUN domain (comprised of the RPIP8, UNC-14, and NESCA proteins) has been suggested to be implicated in small GTPase-mediated membrane trafficking and cell polarity. Accumulating evidence supports the hypothesis that the RUN domain-containing proteins might be responsible for an interaction with a filamentous network linked to actin cytoskeleton and/or microtubules. In addition, several downstream molecules of PI3K are involved in regulation of the membrane trafficking by interacting with vesicle-associated RUN proteins such as RUFY family proteins. In this review, we summarize the background of RUN domain research with an emphasis on the interaction between RUN domain proteins including RUFY proteins (designated as RUN and FYVE domain-containing proteins) and several small GTPases with respect to the regulation of cell polarity and membrane trafficking on filamentous network.

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“…Rusc1 and Rusc2 both contain a RUN domain and a C-terminal SH3 domain. The shortest isoform of Rusc1, namely Nesca, is involved in the neurotrophin signaling pathway (MacDonald et al, 2012;Sun et al, 2012). The function of Rusc2 is not known.…”

Section: Introductionmentioning

confidence: 99%

Members of the Rusc protein family interact with Sufu and inhibit vertebrate Hedgehog signaling

Jin

Schwend

et al. 2016

Development

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Hedgehog (Hh) signaling is fundamentally important for development and adult tissue homeostasis. It is well established that in vertebrates Sufu directly binds and inhibits Gli proteins, the downstream mediators of Hh signaling. However, it is unclear how the inhibitory function of Sufu towards Gli is regulated. Here we report that the Rusc family of proteins, the biological functions of which are poorly understood, form a heterotrimeric complex with Sufu and Gli. Upon Hh signaling, Rusc is displaced from this complex, followed by dissociation of Gli from Sufu. In mammalian fibroblast cells, knockdown of Rusc2 potentiates Hh signaling by accelerating signaling-induced dissociation of the Sufu-Gli protein complexes. In Xenopus embryos, knockdown of Rusc1 or overexpression of a dominant-negative Rusc enhances Hh signaling during eye development, leading to severe eye defects. Our study thus uncovers a novel regulatory mechanism controlling the response of cells to Hh signaling in vertebrates.

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Crystal structure and functional implication of the RUN domain of human NESCA

Cited by 7 publications

References 30 publications

Crystal structure of the FYCO1 RUN domain suggests possible interfaces with small GTPases

Crystal structure of the FYCO1 RUN domain suggests possible interfaces with small GTPases

RUFY, Rab and Rap Family Proteins Involved in a Regulation of Cell Polarity and Membrane Trafficking

Members of the Rusc protein family interact with Sufu and inhibit vertebrate Hedgehog signaling

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