scholarly journals Hexa-Longin domain scaffolds for inter-Rab signalling

2019 ◽  
Author(s):  
Luis Sanchez-Pulido ◽  
Chris P Ponting
Keyword(s):  
Primary Cilia ◽  
Guanine Nucleotide Exchange Factors ◽  
Vesicular Trafficking ◽  
Small Gtpase ◽  
Supplementary Information ◽  
Rab Gtpases ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Hermansky Pudlak Syndrome

Abstract Summary CPLANE is a protein complex required for assembly and maintenance of primary cilia. It contains several proteins, such as INTU, FUZ, WDPCP, JBTS17 and RSG1 (REM2- and RAB-like small GTPase 1), whose genes are mutated in ciliopathies. Using two contrasting evolutionary analyses, coevolution-based contact prediction and sequence conservation, we first identified the INTU/FUZ heterodimer as a novel member of homologous HerMon (Hermansky-Pudlak syndrome and MON1-CCZ1) complexes. Subsequently, we identified homologous Longin domains that are triplicated in each of these six proteins (MON1A, CCZ1, HPS1, HPS4, INTU and FUZ). HerMon complexes are known to be Rab effectors and Rab GEFs (Guanine nucleotide Exchange Factors) that regulate vesicular trafficking. Consequently, INTU/FUZ, their homologous complex, is likely to act as a GEF during activation of Rab GTPases involved in ciliogenesis. Supplementary information Supplementary data are available at Bioinformatics online.

The GAP1 family of GTPase-activating proteins: spatial and temporal regulators of small GTPase signalling

2006 ◽  
Vol 34 (5) ◽  
pp. 846-850 ◽  
Author(s):  
S. Yarwood ◽  
D. Bouyoucef-Cherchalli ◽  
P.J. Cullen ◽  
S. Kupzig
Keyword(s):  
Control Cell ◽  
Guanine Nucleotide Exchange Factors ◽  
Small Gtpase ◽  
Nucleotide Exchange ◽  
Ras Proteins ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Gtpase Activating Proteins ◽  
Oncogenic Mutations ◽  
Hydrolysis Of

Ras proteins are binary switches that, by cycling between inactive GDP-bound and active GTP-bound conformations, regulate multiple cellular signalling pathways including those that control cell growth, differentiation and survival. Approximately 30% of all human tumours express Ras-containing oncogenic mutations that lock the protein into a constitutively active conformation. The activation status of Ras is regulated by two groups of proteins: GEFs (guanine nucleotide-exchange factors) bind to Ras and enhance the exchange of GDP for GTP, thereby activating it, whereas GAPs (GTPase-activating proteins) inactivate Ras by binding to the GTP-bound form and enhancing the hydrolysis of the bound nucleotide back to GDP. In this review, we focus on a group of key regulators of Ras inactivation, the GAP1 family of Ras-GAPs. The members of this family are GAP1m, GAP1IP4BP, CAPRI (Ca2+-promoted Ras inactivator) and RASAL (Ras-GTPase-activating-like protein) and, as we will discuss, they are emerging as important modulators of Ras and small GTPase signalling that are subject to regulation by a diverse array of events and second messenger signals.

scholarly journals Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS–SOS1 interaction

2019 ◽  
Vol 116 (7) ◽  
pp. 2551-2560 ◽  
Author(s):  
Roman C. Hillig ◽  
Brice Sautier ◽  
Jens Schroeder ◽  
Dieter Moosmayer ◽  
André Hilpmann ◽  
...  
Keyword(s):  
Mode Of Action ◽  
Bound State ◽  
Guanine Nucleotide Exchange Factors ◽  
Small Gtpase ◽  
Occurrence Rate ◽  
Nucleotide Exchange ◽  
Downstream Signaling ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Ras Activation

Since the late 1980s, mutations in the RAS genes have been recognized as major oncogenes with a high occurrence rate in human cancers. Such mutations reduce the ability of the small GTPase RAS to hydrolyze GTP, keeping this molecular switch in a constitutively active GTP-bound form that drives, unchecked, oncogenic downstream signaling. One strategy to reduce the levels of active RAS is to target guanine nucleotide exchange factors, which allow RAS to cycle from the inactive GDP-bound state to the active GTP-bound form. Here, we describe the identification of potent and cell-active small-molecule inhibitors which efficiently disrupt the interaction between KRAS and its exchange factor SOS1, a mode of action confirmed by a series of biophysical techniques. The binding sites, mode of action, and selectivity were elucidated using crystal structures of KRASG12C–SOS1, SOS1, and SOS2. By preventing formation of the KRAS–SOS1 complex, these inhibitors block reloading of KRAS with GTP, leading to antiproliferative activity. The final compound 23 (BAY-293) selectively inhibits the KRAS–SOS1 interaction with an IC50 of 21 nM and is a valuable chemical probe for future investigations.

scholarly journals The Regulation of Rab GTPases by Phosphorylation

Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1340
Author(s):  
Lejia Xu ◽  
Yuki Nagai ◽  
Yotaro Kajihara ◽  
Genta Ito ◽  
Taisuke Tomita
Keyword(s):  
Small Gtpases ◽  
Guanine Nucleotide Exchange Factors ◽  
Effector Proteins ◽  
Regulatory Proteins ◽  
Rab Proteins ◽  
Rab Gtpases ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Gtpase Activating Proteins

Rab proteins are small GTPases that act as molecular switches for intracellular vesicle trafficking. Although their function is mainly regulated by regulatory proteins such as GTPase-activating proteins and guanine nucleotide exchange factors, recent studies have shown that some Rab proteins are physiologically phosphorylated in the switch II region by Rab kinases. As the switch II region of Rab proteins undergoes a conformational change depending on the bound nucleotide, it plays an essential role in their function as a ‘switch’. Initially, the phosphorylation of Rab proteins in the switch II region was shown to inhibit the association with regulatory proteins. However, recent studies suggest that it also regulates the binding of Rab proteins to effector proteins, determining which pathways to regulate. These findings suggest that the regulation of the Rab function may be more dynamically regulated by phosphorylation than just through the association with regulatory proteins. In this review, we summarize the recent findings and discuss the physiological and pathological roles of Rab phosphorylation.

scholarly journals The p24 Complex Contributes to Specify Arf1 for COPI Coat Selection

2021 ◽  
Vol 22 (1) ◽  
pp. 423
Author(s):  
Susana Sabido-Bozo ◽  
Ana Maria Perez-Linero ◽  
Javier Manzano-Lopez ◽  
Sofia Rodriguez-Gallardo ◽  
Auxiliadora Aguilera-Romero ◽  
...  
Keyword(s):  
Guanine Nucleotide Exchange Factors ◽  
Small Gtpase ◽  
Nucleotide Exchange ◽  
Vesicle Budding ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Cargo Transport ◽  
Golgi Compartment ◽  
Copi Vesicle ◽  
Golgi Network

Golgi trafficking depends on the small GTPase Arf1 which, upon activation, drives the assembly of different coats onto budding vesicles. Two related types of guanine nucleotide exchange factors (GEFs) activate Arf1 at different Golgi sites. In yeast, Gea1 in the cis-Golgi and Gea2 in the medial-Golgi activate Arf1 to form COPI­coated vesicles for retrograde cargo sorting, whereas Sec7 generates clathrin/adaptor­coated vesicles at the trans-Golgi network (TGN) for forward cargo transport. A central question is how the same activated Arf1 protein manages to assemble different coats depending on the donor Golgi compartment. A previous study has postulated that the interaction between Gea1 and COPI would channel Arf1 activation for COPI vesicle budding. Here, we found that the p24 complex, a major COPI vesicle cargo, promotes the binding of Gea1 with COPI by increasing the COPI association to the membrane independently of Arf1 activation. Furthermore, the p24 complex also facilitates the interaction of Arf1 with its COPI effector. Therefore, our study supports a mechanism by which the p24 complex contributes to program Arf1 activation by Gea1 for selective COPI coat assembly at the cis-Golgi compartment.

scholarly journals The two TRAPP complexes of metazoans have distinct roles and act on different Rab GTPases

2017 ◽  
Vol 217 (2) ◽  
pp. 601-617 ◽  
Author(s):  
Falko Riedel ◽  
Antonio Galindo ◽  
Nadine Muschalik ◽  
Sean Munro
Keyword(s):  
Drosophila Melanogaster ◽  
Guanine Nucleotide Exchange Factors ◽  
Rab Gtpase ◽  
Rab Gtpases ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Core Set ◽  
Protein Particle

Originally identified in yeast, transport protein particle (TRAPP) complexes are Rab GTPase exchange factors that share a core set of subunits. TRAPPs were initially found to act on Ypt1, the yeast orthologue of Rab1, but recent studies have found that yeast TRAPPII can also activate the Rab11 orthologues Ypt31/32. Mammals have two TRAPP complexes, but their role is less clear, and they contain subunits that are not found in the yeast complexes but are essential for cell growth. To investigate TRAPP function in metazoans, we show that Drosophila melanogaster have two TRAPP complexes similar to those in mammals and that both activate Rab1, whereas one, TRAPPII, also activates Rab11. TRAPPII is not essential but becomes so in the absence of the gene parcas that encodes the Drosophila orthologue of the SH3BP5 family of Rab11 guanine nucleotide exchange factors (GEFs). Thus, in metazoans, Rab1 activation requires TRAPP subunits not found in yeast, and Rab11 activation is shared by TRAPPII and an unrelated GEF that is metazoan specific.

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