Biochemical Insight into Novel Rab-GEF Activity of the Mammalian TRAPPIII Complex

Harris, Noah J; Jenkins, Meredith L.; Dalwadi, Udit; Fleming, Kaelin D; Nam, Sung-Eun; Parson, Matthew AH; Yip, Calvin K.; Burke, John E.

doi:10.1016/j.jmb.2021.167145

Cited by 11 publications

(11 citation statements)

References 52 publications

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“…It is known that COPII as well as TRAPPIII complex proteins, which are both elevated in SCZ/BP synapses (Fig. 4G), can promote autophagy during nutrient stress (Tan et al, 2013;Jeong et al, 2018;Harris et al, 2021). These findings suggest that autophagy may be activated at SCZ and BP synapses.…”

Section: Autophagy-related Pathways Are Increased In Scz and Bp Synapsesmentioning

confidence: 71%

Deep proteomics identifies shared molecular pathway alterations in synapses of schizophrenia and bipolar disorder patients and mouse model

Aryal

Bonanno

Song

et al. 2022

Preprint

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Synaptic dysfunction is implicated in the pathophysiology of schizophrenia (SCZ) and bipolar disorder (BP). We used quantitative mass-spectrometry to carry out deep and unbiased profiling of the proteome of synapses purified from the dorsolateral prefrontal cortex of 35 cases of SCZ, 35 cases of BP, and 35 controls. Compared to controls, SCZ and BP synapses showed substantial and similar proteomic alterations. Network and gene set enrichment analyses revealed upregulation of proteins associated with autophagy and certain vesicle transport pathways, and downregulation of proteins related to synaptic, mitochondrial, and ribosomal function in the synapses of individuals with SCZ or BP. Some of the same pathways (e.g., upregulation of vesicle transport, downregulation of mitochondrial and ribosomal proteins) were similarly dysregulated in the synaptic proteome of mutant mice deficient in Akap11, a recently discovered shared risk gene for SCZ and BP. Our work provides novel biological insights into molecular dysfunction at the synapse in SCZ and BP and serves as a resource for understanding the pathophysiology of these debilitating neuropsychiatric disorders.

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Section: Autophagy-related Pathways Are Increased In Scz and Bp Synapsesmentioning

confidence: 71%

Deep proteomics identifies shared molecular pathway alterations in synapses of schizophrenia and bipolar disorder patients and mouse model

Aryal

Bonanno

Song

et al. 2022

Preprint

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“…Metazoan TRAPP complexes share some key features of the budding yeast TRAPP complexes but there are some important differences in their composition and architecture. Other Rabs that are closely related to Rab1 and Rab11 are present in metazoans, and there is biochemical evidence that metazoan TRAPP complexes may act on related Rab substrates in addition to Rab1 and Rab11 but these findings await physiological validation [64,65]. Across organisms, Rab11 homologs have longer HVD tails than do Rab1 homologs, suggesting that the steric gating mechanism could be conserved outside of budding yeast, but determining whether this is the case will require direct experimental tests.…”

Section: Discussionmentioning

confidence: 99%

“…The modest resolution of the structure precluded a detailed analysis of the interface between the TRAPPC8, TRAPPC11, TRAPPC12, and TRAPPC13 subunits. A low-resolution negative-stain structure of the human TRAPPIII complex has also been determined and validated using HDX experiments [64], revealing that it shares high structural similarity with the Drosophila TRAPPIII complex.…”

Section: Metazoan Trappiiimentioning

confidence: 99%

The TRAPP complexes: discriminating GTPases in context

Bagde

Fromme

2022

FEBS Letters

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Correct localization of Rab GTPases in cells is critical for proper function in membrane trafficking. Guanine‐nucleotide exchange factors (GEFs) act as the primary determinants of Rab localization by activating and stabilizing their Rab substrates on specific organelle and vesicle membranes. The TRAPP complexes TRAPPII and TRAPPIII are two related GEFs that use the same catalytic site to activate distinct Rabs, Rab11 and Rab1, respectively. The Rab C‐terminal hypervariable domain (HVD) is an important specificity determinant for the budding yeast TRAPP complexes, with the length of the HVD playing a critical role in counter‐selection. Several recent studies have used cryo‐EM to illuminate how the yeast and metazoan TRAPP complexes identify and activate their substrates. This review summarizes recently characterized Rab substrate selection mechanisms and highlights how the membrane surface provides critical context for the GEF‐GTPase interactions.

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“…The TRAPP complexes have also been reported to be GEFs for other Rab1‐ and Rab11‐related Rabs. In vitro , TRAPPIII has shown GEF activity on Rab43, which belong to the Rab1 family [ 32 ], while TRAPPII has been reported to also activate Rab1, and the Rab1 family relatives, Rab19 and Rab43 [ 33 ]. Guanine nucleotide exchange factors can be promiscuous in vitro , and so determining the physiological importance of these activities will require further investigation.…”

Section: The Substrates Of the Trapp Complex ...mentioning

confidence: 99%

“…The sequences of the two specific subunits of the TRAPPII complex, TRAPPC9 and TRAPPC10, are distantly related to those of TRAPPC8 and TRAPPC11, respectively [ 31 , 38 , 66 ]. These pairs of subunits are thus likely to have arisen by gene duplication in a eukaryotic precursor, which is reflected in the low‐resolution 3D map of metazoan TRAPPII having a similar overall architecture to that of TRAPPIII, with the TRAPP core attached to two arms [ 32 , 51 ]. These arms connect at their opposite ends to form an irregular triangle (Fig.…”

Section: The Architecture Of the Trapp Complexesmentioning

confidence: 99%

The TRAPP complexes: oligomeric exchange factors that activate the small GTPases Rab1 and Rab11

Galindo

Munro

2022

FEBS Letters

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The Transport Protein Particle (TRAPP) complexes are highly conserved multisubunit complexes that act as nucleotide exchange factors (GEFs) for Rab GTPases. They act in both protein secretion and autophagy and have also been proposed to have a role in other processes such as cytokinesis and ciliogenesis. There are two TRAPP complexes in metazoans: TRAPPII, which activates Rab11; and TRAPPIII, which activates Rab1. Both complexes share a core of small subunits that form the active site for the exchange of GDP for GTP. In addition, each TRAPP complex has distinct large subunits that determine the specificity of each complex towards its substrate Rab and are essential for activity in vivo. Crystal structures have revealed the organisation of the TRAPP core and the mechanism of Rab1 activation, whilst recent cryo‐EM structures have unveiled the arrangement of the specific subunits around the core to form each complex. Combining these findings with functional experiments has allowed the proposal of mechanisms for how the specificity of each complex towards their cognate Rab is determined and for the arrangement of these large complexes on the membrane.

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Biochemical Insight into Novel Rab-GEF Activity of the Mammalian TRAPPIII Complex

Cited by 11 publications

References 52 publications

Deep proteomics identifies shared molecular pathway alterations in synapses of schizophrenia and bipolar disorder patients and mouse model

Deep proteomics identifies shared molecular pathway alterations in synapses of schizophrenia and bipolar disorder patients and mouse model

The TRAPP complexes: discriminating GTPases in context

The TRAPP complexes: oligomeric exchange factors that activate the small GTPases Rab1 and Rab11

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