Longin domain GAP complexes in nutrient signalling, membrane traffic and neurodegeneration

Abstract

Small GTPases act as molecular switches and control numerous cellular processes by their binding and hydrolysis of guanosine triphosphate (GTP). The activity of small GTPases is coordinated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). Recent structural and functional studies have characterized a subset of GAPs whose catalytic units consist of longin domains. Longin domain containing GAPs regulate small GTPases that facilitate nutrient signalling, autophagy, vesicular trafficking and lysosome homeostasis. All known examples in this GAP family function as part of larger multiprotein complexes. The three characterized mammalian protein complexes in this class are FLCN:FNIP, GATOR1 and C9orf72:SMCR8. Each complex carries out a unique cellular function by regulating distinct small GTPases. In this article, we explore the roles of longin domain GAPs in nutrient sensing, membrane dynamic, vesicular trafficking and disease. Through a structural lens, we examine the mechanism of each longin domain GAP and highlight potential therapeutic applications.

Diversity, origin, and evolution of the ESCRT systems

“…Assuming that Vps28-C interacts with ESCRT-II, these proteins could associate with ESCRT-II without the involvement of any core ESCRT-I subunits. The presence of longin suggests that these proteins can activate small GTPases, which regulate many cellular pathways related to nutrient signaling and vesicular trafficking ( 68 ). Additional domains found in these proteins include TPR repeats, IG-like domains, and HTH/PCI domains which can be involved in interactions with protein substrates for further trafficking ( 69 – 71 ).…”

A pathogenic variant in the FLCN gene presenting with pure dementia: is autophagy at the intersection between neurodegeneration and cancer?

“…No interactions have been yet detected for C9orf72 with either FLCN and FNIP1-2, indicating that there is specificity for the formation of two distinct complexes within this subfamily of DENN domain proteins: the FLCN/FNIP1-2 complex and the C9orf72/SMCR8/WDR41 complex (Amick et al, 2016). The structural orientation of the C9orf72/SMCR8/WDR41 complex is also reminiscent of FLCN/FNIP1-2, which suggested it might possess GAP activity (Jansen and Hurley, 2023). Then, these two different protein ensembles act at lysosomes with functions that seem related but distinct and that have yet to be elucidated (Amick and Ferguson, 2017;Jansen and Hurley, 2023; Figure 1C).…”

Small GTPase signaling hubs at the surface of cellular membranes in physiology and disease

“…An exception to this rule are GAPs that contain longin/roadblock domains, which inactivate different GTPases: GTPase‐activating protein activity toward Rags (GATOR)1 and folliculin (FLCN)/FNIP in mechanismic target of rapamycin (mTOR)C‐controlled nutrient signaling, which inactivate the atypical RagA and RagC GTPases, respectively, the C9orf72:SMCR8 complex, a newly discovered GAP for trafficking Arf GTPases involved in amyotrophic lateral sclerosis, and mutual gliding‐motility protein B [MglB], which inactivates the bacterial small GTPase MglA to control bacterial motility. Jansen and Hurley discuss how cryo‐EM revealed that both GATOR1 and FLCN/FNIP, though binding to their cognate Rag GTPases in distinct manners, have both an inhibitory and a productive binding mode, predicted to respond to an increase or decrease in nutrients [7]. By contrast, the orientation of the longin domain of C9orf72 with respect to Arf is reminiscent of FLCN/folliculin‐interacting protein, which led to the hypothesis, then the confirmation using purified proteins, that it is an ArfGAP [7].…”

“…Jansen and Hurley discuss how cryo-EM revealed that both GATOR1 and FLCN/FNIP, though binding to their cognate Rag GTPases in distinct manners, have both an inhibitory and a productive binding mode, predicted to respond to an increase or decrease in nutrients [7]. By contrast, the orientation of the longin domain of C9orf72 with respect to Arf is reminiscent of FLCN/ folliculin-interacting protein, which led to the hypothesis, then the confirmation using purified proteins, that it is an ArfGAP [7]. As discussed by Dinet and Mignot, bacterial MglB is also an atypical GAP that can bind to MglA in both an inhibitory and a productive manner, with the remarkable property that it is upregulated by MglA-GDP [15].…”

“…We are now delighted to present 13 articles that highlight how integrated structural, biochemical, and biophysical approaches have allowed to shed light on the mechanisms of fundamental functions of major members of this superfamily. Notably, these reviews show how several experimental approaches that were rarely used a decade ago, are now taking center stage in moving the field forward: reconstitutions of small GTPase systems in artificial membranes [5][6][7][8][9], single particle cryo-electron microscopy [5][6][7][9][10][11][12], 3D electron tomography reconstructions [12], or optogenetics [13]. Of these, Loose and coauthors present a great overview of the power and inherent difficulties of in vitro reconstitutions using biomimetic membranes, and how they have revealed in a quantitative manner the inner workings of intricate small GTPase networks, which would have been unattainable in vivo [8].…”