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Article ; Online: SHOCing RAF into action.

Mott, Helen R / Owen, Darerca

2022 Volume 29, Issue 10, Page(s) 958–960

Language	English
Publishing date	2022-10-17
Publishing country	United States
Document type	Journal Article
ZDB-ID	2126708-X
ISSN	1545-9985 ; 1545-9993
ISSN (online)	1545-9985
ISSN	1545-9993
DOI	10.1038/s41594-022-00843-2
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Article: Membrane extraction by calmodulin underpins the disparate signalling of RalA and RalB

Chamberlain, Samuel G. / Owen, Darerca / Mott, Helen R.

BioEssays. 2022 June, v. 44, no. 6

2022

Abstract: Both RalA and RalB interact with the ubiquitous calcium sensor, calmodulin (CaM). New structural and biophysical characterisation of these interactions strongly suggests that, in the native membrane‐associated state, only RalA can be extracted from the ... ...

Abstract	Both RalA and RalB interact with the ubiquitous calcium sensor, calmodulin (CaM). New structural and biophysical characterisation of these interactions strongly suggests that, in the native membrane‐associated state, only RalA can be extracted from the membrane by CaM and this non‐canonical interaction could underpin the divergent signalling roles of these closely related GTPases. The isoform specificity for RalA exhibited by CaM is hypothesised to contribute to the disparate signalling roles of RalA and RalB in mitochondrial dynamics. This would lead to CaM shuttling RalA to the mitochondrial membrane but leaving RalB localisation unperturbed, and in doing so triggering mitochondrial fission pathways rather than mitophagy.
Keywords	calcium ; calmodulin ; guanosinetriphosphatase ; mitochondria ; mitochondrial membrane ; mitophagy
Language	English
Dates of publication	2022-06
Publishing place	John Wiley & Sons, Ltd
Document type	Article
Note	JOURNAL ARTICLE
ZDB-ID	50140-2
ISSN	1521-1878 ; 0265-9247
ISSN (online)	1521-1878
ISSN	0265-9247
DOI	10.1002/bies.202200011
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Article ; Online: Membrane extraction by calmodulin underpins the disparate signalling of RalA and RalB.

Chamberlain, Samuel G / Owen, Darerca / Mott, Helen R

BioEssays : news and reviews in molecular, cellular and developmental biology

2022 Volume 44, Issue 6, Page(s) e2200011

Abstract: Both RalA and RalB interact with the ubiquitous calcium sensor, calmodulin (CaM). New structural and biophysical characterisation of these interactions strongly suggests that, in the native membrane-associated state, only RalA can be extracted from the ... ...

Abstract	Both RalA and RalB interact with the ubiquitous calcium sensor, calmodulin (CaM). New structural and biophysical characterisation of these interactions strongly suggests that, in the native membrane-associated state, only RalA can be extracted from the membrane by CaM and this non-canonical interaction could underpin the divergent signalling roles of these closely related GTPases. The isoform specificity for RalA exhibited by CaM is hypothesised to contribute to the disparate signalling roles of RalA and RalB in mitochondrial dynamics. This would lead to CaM shuttling RalA to the mitochondrial membrane but leaving RalB localisation unperturbed, and in doing so triggering mitochondrial fission pathways rather than mitophagy.
MeSH term(s)	Calmodulin/metabolism ; GTP Phosphohydrolases/metabolism ; Protein Isoforms/metabolism ; Signal Transduction
Chemical Substances	Calmodulin ; Protein Isoforms ; GTP Phosphohydrolases (EC 3.6.1.-)
Language	English
Publishing date	2022-03-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	50140-2
ISSN	1521-1878 ; 0265-9247
ISSN (online)	1521-1878
ISSN	0265-9247
DOI	10.1002/bies.202200011
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Article: RLIP76: A Structural and Functional Triumvirate.

Cornish, Jasmine / Owen, Darerca / Mott, Helen R

Cancers

2021 Volume 13, Issue 9

Abstract: RLIP76/RalBP1 is an ATP-dependent transporter of glutathione conjugates, which is overexpressed in various human cancers, but its diverse functions in normal cells, which include endocytosis, stress response and mitochondrial dynamics, are still not ... ...

Abstract	RLIP76/RalBP1 is an ATP-dependent transporter of glutathione conjugates, which is overexpressed in various human cancers, but its diverse functions in normal cells, which include endocytosis, stress response and mitochondrial dynamics, are still not fully understood. The protein can be divided into three distinct regions, each with its own structural properties. At the centre of the protein are two well-defined domains, a GTPase activating protein domain targeting Rho family small G proteins and a small coiled-coil that binds to the Ras family small GTPases RalA and RalB. In engaging with Rho and Ral proteins, RLIP76 bridges these two distinct G protein families. The N-terminal region is predicted to be disordered and is rich in basic amino acids, which may mediate membrane association, consistent with its role in transport. RLIP76 is an ATP-dependent transporter with ATP-binding sites within the N-terminus and the Ral binding domain. Furthermore, RLIP76 is subject to extensive phosphorylation, particularly in the N-terminal region. In contrast, the C-terminal region is thought to form an extensive coiled-coil that could mediate dimerization. Here, we review the structural features of RLIP76, including experimental data and computational predictions, and discuss the implications of its various post-translational modifications.
Language	English
Publishing date	2021-05-04
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers13092206
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Article ; Online: Progress in the therapeutic inhibition of Cdc42 signalling.

Murphy, Natasha P / Mott, Helen R / Owen, Darerca

Biochemical Society transactions

2021 Volume 49, Issue 3, Page(s) 1443–1456

Abstract: Cdc42 is a member of the Rho family of small GTPases and a key regulator of the actin cytoskeleton, controlling cell motility, polarity and cell cycle progression. It signals downstream of the master regulator Ras and is essential for cell transformation ...

Abstract	Cdc42 is a member of the Rho family of small GTPases and a key regulator of the actin cytoskeleton, controlling cell motility, polarity and cell cycle progression. It signals downstream of the master regulator Ras and is essential for cell transformation by this potent oncogene. Overexpression of Cdc42 is observed in several cancers, where it is linked to poor prognosis. As a regulator of both cell architecture and motility, deregulation of Cdc42 is also linked to tumour metastasis. Like Ras, Cdc42 and other components of the signalling pathways it controls represent important potential targets for cancer therapeutics. In this review, we consider the progress that has been made targeting Cdc42, its regulators and effectors, including new modalities and new approaches to inhibition. Strategies under consideration include inhibition of lipid modification, modulation of Cdc42-GEF, Cdc42-GDI and Cdc42-effector interactions, and direct inhibition of downstream effectors.
MeSH term(s)	Actin Cytoskeleton/metabolism ; Aminoquinolines/therapeutic use ; Animals ; Benzamides/therapeutic use ; Benzazepines/therapeutic use ; Humans ; Molecular Targeted Therapy/methods ; Neoplasms/drug therapy ; Neoplasms/genetics ; Neoplasms/metabolism ; Oximes/therapeutic use ; Protein Binding/drug effects ; Pyrazoles/therapeutic use ; Pyrimidines/therapeutic use ; Signal Transduction/drug effects ; Signal Transduction/genetics ; Signal Transduction/physiology ; Sulfonamides/therapeutic use ; Thiourea/analogs & derivatives ; Thiourea/therapeutic use ; cdc42 GTP-Binding Protein/antagonists & inhibitors ; cdc42 GTP-Binding Protein/genetics ; cdc42 GTP-Binding Protein/metabolism
Chemical Substances	Aminoquinolines ; Benzamides ; Benzazepines ; CID2950007 ; NSC 23766 ; Oximes ; Pyrazoles ; Pyrimidines ; Sulfonamides ; ZCL278 ; secramine A ; CDC42 protein, human (EC 3.6.5.2) ; cdc42 GTP-Binding Protein (EC 3.6.5.2) ; Thiourea (GYV9AM2QAG)
Language	English
Publishing date	2021-06-07
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	184237-7
ISSN	1470-8752 ; 0300-5127
ISSN (online)	1470-8752
ISSN	0300-5127
DOI	10.1042/BST20210112
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Article ; Online: The structure and function of protein kinase C-related kinases (PRKs).

Sophocleous, Georgios / Owen, Darerca / Mott, Helen R

Biochemical Society transactions

2021 Volume 49, Issue 1, Page(s) 217–235

Abstract: The protein kinase C-related kinase (PRK) family of serine/threonine kinases, PRK1, PRK2 and PRK3, are effectors for the Rho family small G proteins. An array of studies have linked these kinases to multiple signalling pathways and physiological roles, ... ...

Abstract	The protein kinase C-related kinase (PRK) family of serine/threonine kinases, PRK1, PRK2 and PRK3, are effectors for the Rho family small G proteins. An array of studies have linked these kinases to multiple signalling pathways and physiological roles, but while PRK1 is relatively well-characterized, the entire PRK family remains understudied. Here, we provide a holistic overview of the structure and function of PRKs and describe the molecular events that govern activation and autoregulation of catalytic activity, including phosphorylation, protein interactions and lipid binding. We begin with a structural description of the regulatory and catalytic domains, which facilitates the understanding of their regulation in molecular detail. We then examine their diverse physiological roles in cytoskeletal reorganization, cell adhesion, chromatin remodelling, androgen receptor signalling, cell cycle regulation, the immune response, glucose metabolism and development, highlighting isoform redundancy but also isoform specificity. Finally, we consider the involvement of PRKs in pathologies, including cancer, heart disease and bacterial infections. The abundance of PRK-driven pathologies suggests that these enzymes will be good therapeutic targets and we briefly report some of the progress to date.
MeSH term(s)	Animals ; Catalysis ; Humans ; Protein Conformation ; Protein Kinase C/chemistry ; Protein Kinases/chemistry ; Protein Kinases/physiology ; Signal Transduction/physiology ; Structure-Activity Relationship
Chemical Substances	Protein Kinases (EC 2.7.-) ; Protein Kinase C (EC 2.7.11.13)
Language	English
Publishing date	2021-09-24
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	184237-7
ISSN	1470-8752 ; 0300-5127
ISSN (online)	1470-8752
ISSN	0300-5127
DOI	10.1042/BST20200466
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Article ; Online: ACKnowledging the role of the Activated-Cdc42 associated kinase (ACK) in regulating protein stability in cancer.

Hodder, Samantha / Fox, Millie / Binti Ahmad Mokhtar, Ana Masara / Mott, Helen R / Owen, Darerca

Small GTPases

2023 Volume 14, Issue 1, Page(s) 14–25

Abstract: Activated Cdc42-associated kinase (ACK), a non-receptor tyrosine kinase, is an effector for the small GTPase Cdc42. ACK is emerging as an important component of the cancer landscape and thus, a promising target for the treatment of many malignancies. ACK ...

Abstract	Activated Cdc42-associated kinase (ACK), a non-receptor tyrosine kinase, is an effector for the small GTPase Cdc42. ACK is emerging as an important component of the cancer landscape and thus, a promising target for the treatment of many malignancies. ACK is also being increasingly recognized as a potentially influential player in the regulation of protein homoeostasis. The delicate equilibrium between protein synthesis and protein degradation is crucial for healthy cell function and dysregulation of protein homoeostasis is a common occurrence in human disease. Here, we review the molecular mechanisms by which ACK regulates the stability of diverse cellular proteins (e.g. EGFR, p27, p53, p85 isoforms and RhoGDI-3), some of which rely on the kinase activity of ACK while others, interestingly, do not. Ultimately, further research will be required to bridge our knowledge gaps and determine if ACK regulates the stability of further cellular proteins but collectively, such mechanistic interrogation would contribute to determining whether ACK is a promising target for anti-cancer therapy. In therapeutics, proteasome inhibitors are an efficacious but problematic class of drugs. Targeting other modulators of proteostasis, like ACK, could open novel avenues for intervention.
MeSH term(s)	Humans ; cdc42 GTP-Binding Protein/metabolism ; Neoplasms ; Phosphorylation ; Protein Stability ; Protein-Tyrosine Kinases/metabolism
Chemical Substances	cdc42 GTP-Binding Protein (EC 3.6.5.2) ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; TNK2 protein, human (EC 2.7.10.2)
Language	English
Publishing date	2023-06-01
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2682247-7
ISSN	2154-1256 ; 2154-1248
ISSN (online)	2154-1256
ISSN	2154-1248
DOI	10.1080/21541248.2023.2212573
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Article ; Online: CRIB effector disorder: exquisite function from chaos.

Owen, Darerca / Mott, Helen R

Biochemical Society transactions

2018 Volume 46, Issue 5, Page(s) 1289–1302

Abstract: The CRIB (Cdc42/Rac interactive binding) family of small G-protein effectors contain significant regions with intrinsic disorder. The G-protein-binding regions are contained within these intrinsically disordered regions. Most CRIB proteins also contain ... ...

Abstract	The CRIB (Cdc42/Rac interactive binding) family of small G-protein effectors contain significant regions with intrinsic disorder. The G-protein-binding regions are contained within these intrinsically disordered regions. Most CRIB proteins also contain stretches of basic residues associated with their G-protein-binding regions. The basic region (BR) and G-protein-binding region together allow the CRIB effectors to bind to their cognate G-protein via a dock- and coalesce-binding mechanism. The BRs of these proteins take on multiple roles: steering G-protein binding, interacting with elements of the membrane and regulating intramolecular regulatory interactions. The ability of these regions of the CRIBs to undergo multivalent interactions and mediate charge neutralizations equips them with all the properties required to drive liquid-liquid phase separation and therefore to initiate and drive signalosome formation. It is only recently that the structural plasticity in these proteins is being appreciated as the driving force for these vital cellular processes.
MeSH term(s)	Animals ; GTP Phosphohydrolases/chemistry ; GTP-Binding Proteins/metabolism ; Gene Expression Regulation ; Humans ; Hydrophobic and Hydrophilic Interactions ; Membrane Proteins/metabolism ; Nonlinear Dynamics ; Polylysine/chemistry ; Protein Binding ; Protein Domains ; Protein Structure, Quaternary ; Signal Transduction ; Static Electricity ; Tumor Suppressor Proteins/metabolism ; cdc42 GTP-Binding Protein/metabolism ; rac1 GTP-Binding Protein/metabolism
Chemical Substances	Membrane Proteins ; RAC1 protein, human ; SCRIB protein, human ; Tumor Suppressor Proteins ; Polylysine (25104-18-1) ; GTP Phosphohydrolases (EC 3.6.1.-) ; GTP-Binding Proteins (EC 3.6.1.-) ; CDC42 protein, human (EC 3.6.5.2) ; cdc42 GTP-Binding Protein (EC 3.6.5.2) ; rac1 GTP-Binding Protein (EC 3.6.5.2)
Language	English
Publishing date	2018-08-28
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	184237-7
ISSN	1470-8752 ; 0300-5127
ISSN (online)	1470-8752
ISSN	0300-5127
DOI	10.1042/BST20170570
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Article ; Online: Allostery and dynamics in small G proteins.

Mott, Helen R / Owen, Darerca

Biochemical Society transactions

2018 Volume 46, Issue 5, Page(s) 1333–1343

Abstract: The Ras family of small guanine nucleotide-binding proteins behave as molecular switches: they are switched off and inactive when bound to GDP but can be activated by GTP binding in response to signal transduction pathways. Early structural analysis ... ...

Abstract	The Ras family of small guanine nucleotide-binding proteins behave as molecular switches: they are switched off and inactive when bound to GDP but can be activated by GTP binding in response to signal transduction pathways. Early structural analysis showed that two regions of the protein, which change conformation depending on the nucleotide present, mediate this switch. A large number of X-ray, NMR and simulation studies have shown that this is an over-simplification. The switch regions themselves are highly dynamic and can exist in distinct sub-states in the GTP-bound form that have different affinities for other proteins. Furthermore, regions outside the switches have been found to be sensitive to the nucleotide state of the protein, indicating that allosteric change is more widespread than previously thought. Taken together, the accrued knowledge about small G protein structures, allostery and dynamics will be essential for the design and testing of the next generation of inhibitors, both orthosteric and allosteric, as well as for understanding their mode of action.
MeSH term(s)	Allosteric Site ; Guanine Nucleotide Exchange Factors/metabolism ; Guanosine Diphosphate/metabolism ; Guanosine Triphosphate/metabolism ; Monomeric GTP-Binding Proteins/metabolism ; Mutation ; Protein Binding ; Protein Domains ; Protein Structure, Secondary ; Signal Transduction
Chemical Substances	Guanine Nucleotide Exchange Factors ; Guanosine Diphosphate (146-91-8) ; Guanosine Triphosphate (86-01-1) ; Monomeric GTP-Binding Proteins (EC 3.6.5.2)
Language	English
Publishing date	2018-10-08
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	184237-7
ISSN	1470-8752 ; 0300-5127
ISSN (online)	1470-8752
ISSN	0300-5127
DOI	10.1042/BST20170569
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Article ; Online: Bioblockades join the assault on small G protein signalling.

Mott, Helen R / Owen, Darerca

Seminars in cancer biology

2018 Volume 54, Page(s) 149–161

Abstract: Inhibition of Ras signalling has been a goal almost since its central role in cell signalling and its deregulation in disease were discovered. Early attempts at inhibiting its post-translational modification using peptidomimetics were successful in cell ... ...

Abstract	Inhibition of Ras signalling has been a goal almost since its central role in cell signalling and its deregulation in disease were discovered. Early attempts at inhibiting its post-translational modification using peptidomimetics were successful in cell culture but failed spectacularly in clinical trials, making industry wary of targeting this critical oncoprotein. Small molecule inhibition of the protein-protein interactions involving Ras has also been difficult due to the nature of the interaction interface. Recent improvements in design, synthesis and selection of stabilised peptides, peptidomimetics and macrocycles have suggested that these biologics may represent a new hope in Ras inhibition. Here we review the various ways in which Ras has been targeted with these molecules. We also describe work on related small G proteins of the Ras superfamily, since many of the principles may be applicable to Ras, and these also provide inhibition of pathways downstream of Ras.
MeSH term(s)	Animals ; Drug Discovery ; Humans ; Monomeric GTP-Binding Proteins/chemistry ; Monomeric GTP-Binding Proteins/metabolism ; Multigene Family ; Peptides/chemistry ; Peptides/metabolism ; Protein Binding/drug effects ; Protein Interaction Domains and Motifs ; Protein Transport ; Signal Transduction/drug effects ; Son of Sevenless Proteins/chemistry ; Son of Sevenless Proteins/metabolism ; Structure-Activity Relationship ; ras Proteins/chemistry ; ras Proteins/genetics ; ras Proteins/metabolism
Chemical Substances	Peptides ; Son of Sevenless Proteins ; Monomeric GTP-Binding Proteins (EC 3.6.5.2) ; ras Proteins (EC 3.6.5.2)
Language	English
Publishing date	2018-01-04
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1033980-2
ISSN	1096-3650 ; 1044-579X
ISSN (online)	1096-3650
ISSN	1044-579X
DOI	10.1016/j.semcancer.2018.01.001
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