Bi-allelic mutations in <i>TRAPPC2L</i> result in a neurodevelopmental disorder and have an impact on RAB11 in fibroblasts

Milev, Miroslav P.; Graziano, Claudio; Karall, Daniela; Kuper, Willemijn F. E.; Al-Deri, Noraldin; Cordelli, Duccio Maria; Haack, Tobias B.; Danhauser, Katharina; Iuso, Arcangela; Palombo, Flavia; Pippucci, Tommaso; Prokisch, Holger; Saint‐Dic, Djenann; Seri, Marco; Stanga, Daniela; Cenacchi, Giovanna; Gassen, Koen van; Zschocke, Johannes; Fauth, Christine; Mayr, Johannes A.; Sacher, Michael; Hasselt, Peter M. van

doi:10.1136/jmedgenet-2018-105441

Cited by 42 publications

(43 citation statements)

References 54 publications

(39 reference statements)

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“…https://doi.org/10.1371/journal.pgen.1008557.g005 the core, almost certainly by way of the reported interaction with Trs120 [35,36], playing a role similar to that of Trs33 acting at the opposite side of the core hetero-heptamer. The finding that Tca17 is stably attached to the TRAPPII-specific subcomplex detected in trs20Δ, trs23Δ and trs31Δ mutants ( Figs 5A, 5C and 6A) agrees with reported interactions of Tca17 with Trs130 and Trs65 [13,45].…”

Section: The Trappii-specific Subcomplex Coexists With Incomplete Corsupporting

confidence: 87%

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Characterization of Aspergillus nidulans TRAPPs uncovers unprecedented similarities between fungi and metazoans and reveals the modular assembly of TRAPPII

et al. 2019

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TRAnsport Protein Particle complexes (TRAPPs) are ubiquitous regulators of membrane traffic mediating nucleotide exchange on the Golgi regulatory GTPases RAB1 and RAB11. In S. cerevisiae and metazoans TRAPPs consist of two large oligomeric complexes: RAB11-activating TRAPPII and RAB1-activating TRAPPIII. These share a common core TRAPPI heteroheptamer, absent in metazoans but detected in minor proportions in yeast, likely originating from in vitro-destabilized TRAPPII/III. Despite overall TRAPP conservation, the budding yeast genome has undergone extensive loss of genes, and lacks homologues of some metazoan TRAPP subunits. With nearly twice the total number of genes of S. cerevisiae, another ascomycete Aspergillus nidulans has also been used for studies on TRAPPs. We combined sizefractionation chromatography with single-step purification coupled to mass-spectrometry and negative-stain electron microscopy to establish the relative abundance, composition and architecture of Aspergillus TRAPPs, which consist of TRAPPII and TRAPPIII in a 2:1 proportion, plus a minor amount of TRAPPI. We show that Aspergillus TRAPPIII contains homologues of metazoan TRAPPC11, TRAPPC12 and TRAPPC13 subunits, absent in S. cerevisiae, and establish that these subunits are recruited to the complex by Tca17/TRAPPC2L, which itself binds to the 'Trs33 side' of the complex. Thus Aspergillus TRAPPs compositionally resemble mammalian TRAPPs to a greater extent than those in budding yeast. Exploiting the ability of constitutively-active (GEF-independent, due to accelerated GDP release) RAB1* and RAB11* alleles to rescue viability of null mutants lacking essential TRAPP subunits, we establish that the only essential role of TRAPPs is activating RAB1 and RAB11, and genetically classify each essential subunit according to their role(s) in TRAPPII (TRAPPII-specific subunits) or TRAPPII and TRAPPIII (core TRAPP subunits). Constitutively-active RAB mutant combinations allowed examination of TRAPP composition in mutants lacking essential subunits, which led to the discovery of a stable Trs120/Trs130/Trs65/Tca17 TRAPPII-specific subcomplex whose Trs20-and Trs33-dependent assembly onto core TRAPP generates TRAPPII.

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Section: The Trappii-specific Subcomplex Coexists With Incomplete Corsupporting

confidence: 87%

“…In contrast, in the pathway leading to TRAPPIII assembly Trs20 recruits Trs85 whereas Tca17 recruits TRAPPC11/TRAPPC12/TRAPPC13. This dual role of Tca17 in TRAPPII and TRAP-PIII might help understand how homozygous mutations in the human homologue of Tca17, TRAPPC2L, result in a developmental disorder [45].…”

Section: Discussionmentioning

confidence: 99%

Characterization of Aspergillus nidulans TRAPPs uncovers unprecedented similarities between fungi and metazoans and reveals the modular assembly of TRAPPII

et al. 2019

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“…In 2013, Taussig and colleagues proposed four distinct possible dimerized structures for yeast TRAPPII, favouring two models with subunits Trs130 and Trs65 at the centre of the TRAPPII dimer (Taussig et al ., ). Our yeast two‐hybrid analyses are consistent with reported interactions between Tca17/TRAPPC2L and Trs130/TRAPPC10 (Choi et al ., ; Milev et al ., ). Moreover, binary interactions between AtTRS120 truncations and between AtTRS120 and CLUB/AtTRS130 truncations that are indicated by our yeast two‐hybrid analyses support a model for Arabidopsis TRAPPII structure with dimerized TRS120 at the centre of the complex (Figure ).…”

Section: Discussionmentioning

confidence: 97%

Interactions between Transport Protein Particle (TRAPP) complexes and Rab GTPases in Arabidopsis

et al. 2019

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Transport Protein Particle II (TRAPPII) is essential for exocytosis, endocytosis, protein sorting and cytokinesis. In spite of a considerable understanding of its biological role, little information is known about Arabidopsis TRAPPII complex topology and molecular function. In this study, independent proteomic approaches initiated with TRAPP components or Rab-A GTPase variants converge on the TRAPPII complex. We show that the Arabidopsis genome encodes the full complement of 13 TRAPPC subunits, including four previously unidentified components. A dimerization model is proposed to account for binary interactions between TRAPPII subunits. Preferential binding to dominant negative (GDP-bound) versus wild-type or constitutively active (GTP-bound) RAB-A2a variants discriminates between TRAPPII and TRAPPIII subunits and shows that Arabidopsis complexes differ from yeast but resemble metazoan TRAPP complexes. Analyzes of Rab-A mutant variants in trappii backgrounds provide genetic evidence that TRAPPII functions upstream of RAB-A2a, allowing us to propose that TRAPPII is likely to behave as a guanine nucleotide exchange factor (GEF) for the RAB-A2a GTPase. GEFs catalyze exchange of GDP for GTP; the GTP-bound, activated, Rab then recruits a diverse local network of Rab effectors to specify membrane identity in subsequent vesicle fusion events. Understanding GEFÀRab interactions will be crucial to unravel the co-ordination of plant membrane traffic.280 Monika Kalde et al. c The log 2 intensity ratio for each protein was calculated from its average signal intensity in the experiment divided by its average intensity in the control, which was an empty soluble GFP vector. Detected TRAPP subunits were ranked according to their ratio between the experiment and negative control. The proteins are sorted by rank. Note that TRS65/TRAPPC13, which is a TRAPPII subunit in yeast but a TRAPPIII subunit in metazoans, had an intermediate intensity ratio of 7. 3 (see Figure S1). The high confidence interactors include shared and TRAP-PII-specific subunits. d P-values were calculated using the t-test (two-sided) and are all significant (P < 0.02) with the exception of those for TRAPPIII homologues, which are in red. This table lists only TRAPP components detected in the IPs. Related to Figure S1 on the CLUB interactome.

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“…Mutations in TRAPPC6A, TRAPPC6B, and TRAPPC9 are observed in patients with neurodevelopmental disorders [91][92][93][94]. TRAPPC2L and TRAPPC12 mutations cause encephalopathy [95,96]. Interestingly, fibroblasts prepared from a patient harboring TRAPPC12 mutations showed delayed ER-to-Golgi transport and Golgi fragmentation, which is readily rescued by reintroducing wild-type TRAPPC12, suggesting that these mutations cause loss of function [96].…”

Section: Er-to-golgi Trafficking Defects and Neurological Disordersmentioning

confidence: 99%

ER-to-Golgi Trafficking and Its Implication in Neurological Diseases

Wang

Stanford

Kundu

2020

Cells

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Membrane and secretory proteins are essential for almost every aspect of cellular function. These proteins are incorporated into ER-derived carriers and transported to the Golgi before being sorted for delivery to their final destination. Although ER-to-Golgi trafficking is highly conserved among eukaryotes, several layers of complexity have been added to meet the increased demands of complex cell types in metazoans. The specialized morphology of neurons and the necessity for precise spatiotemporal control over membrane and secretory protein localization and function make them particularly vulnerable to defects in trafficking. This review summarizes the general mechanisms involved in ER-to-Golgi trafficking and highlights mutations in genes affecting this process, which are associated with neurological diseases in humans. OverviewApproximately one-third of all proteins encoded by the mammalian genome are exported from the endoplasmic reticulum (ER) and transported to the Golgi apparatus, where they are sorted for delivery to their final destination in membrane compartments or secretory vesicles [1]. Secretory proteins are co-translationally inserted into the ER and then packaged into transport vesicles at ER exit sites (ERES, also known as the transitional ER), which are specialized regions of smooth ER [1].The stepwise process for segregating and exporting cargo from the ER is similar in yeast, plant, and mammalian cells and relies on several essential proteins (SAR1-GTPase, SEC23, SEC24, SEC13, and SEC31). The first step involves the conversion of SAR1-GDP to SAR1-GTP by the guanine nucleotide exchange factor SEC12, which resides in the ER membrane [2,3]. This results in the localization of SAR1-GTP to the ER membrane, triggering the recruitment of SEC23/24 heterodimers [4]. The membrane localization of the SEC23/24 heterodimers promotes the entrapment of cargo by SEC24 and the recruitment of SEC13/31 heterotetramers. The sequential binding of SEC13/31 heterotetramers to SAR1-GTP-SEC23/24 complexes drives the formation of a cage-like lattice [4][5][6][7]. Although the basic steps involved in generating COPII vesicles are well understood and can be reconstituted in vitro, additional proteins are involved in regulating the process in cells. Differences between yeast and mammalian ER-to-Golgi trafficking include the presence of multiple COPII protein isoforms and an ER-Golgi intermediate compartment (ERGIC) in mammals, which likely evolved to help meet the cell-type-specific demands of multicellular organisms.Unlike other cell types, neurons consist of two compartments: the somatodendritic compartment and the axonal compartment. These compartments are separated by the axonal-exclusion zone located at the base of the axon, where proteins are either permitted into or excluded from the axon. Neurons are

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Bi-allelic mutations in TRAPPC2L result in a neurodevelopmental disorder and have an impact on RAB11 in fibroblasts

Abstract: Our study implicates a RAB11 pathway in the aetiology of the TRAPPC2L disorder and has implications for other TRAPP-related disorders with similar phenotypes.

Cited by 42 publications

References 54 publications

Characterization of Aspergillus nidulans TRAPPs uncovers unprecedented similarities between fungi and metazoans and reveals the modular assembly of TRAPPII

Characterization of Aspergillus nidulans TRAPPs uncovers unprecedented similarities between fungi and metazoans and reveals the modular assembly of TRAPPII

Interactions between Transport Protein Particle (TRAPP) complexes and Rab GTPases in Arabidopsis

ER-to-Golgi Trafficking and Its Implication in Neurological Diseases

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