Signaling pathway of a photoactivable Rac1-GTPase in the early stages

Peter, Emanuel; Dick, Bernhard; Baeurle, Stephan A (2012). Signaling pathway of a photoactivable Rac1-GTPase in the early stages. Proteins - structure, function, and bioinformatics, 80(5), pp. 1350-62. Hoboken, N.J.: Wiley-Blackwell 10.1002/prot.24031

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In modern life- and medical-sciences major efforts are currently concentrated on creating artificial photoenzymes, consisting of light- oxygen-voltage-sensitive (LOV) domains fused to a target enzyme. Such protein constructs possess great potential for controlling the cell metabolism as well as gene function upon light stimulus. This has recently been impressively demonstrated by designing a novel artificial fusion protein, connecting the AsLOV2-Jα-photosensor from Avena sativa with the Rac1-GTPase (AsLOV2-Jα-Rac1), and by using it, to control the motility of cancer cells from the HeLa-line. Although tremendous progress has been achieved on the generation of such protein constructs, a detailed understanding of their signaling pathway after photoexcitation is still in its infancy. Here, we show through computer simulations of the AsLOV2-Jα-Rac1-photoenzyme that the early processes after formation of the Cys450-FMN-adduct involve the breakage of a H-bond between the carbonyl oxygen FMN-C4O and the amino group of Gln513, followed by a rotational reorientation of its sidechain. This initial event is followed by successive events including β-sheet tightening and transmission of torsional stress along the Iβ-sheet, which leads to the disruption of the Jα-helix from the N-terminal end. Finally, this process triggers the detachment of the AsLOV2-Jα-photosensor from the Rac1-GTPase, ultimately enabling the activation of Rac1 via binding of the effector protein PAK1.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Nephrology and Hypertension
UniBE Contributor:	Dick, Bernhard
ISSN:	0887-3585
Publisher:	Wiley-Blackwell
Language:	English
Submitter:	Factscience Import
Date Deposited:	04 Oct 2013 14:42
Last Modified:	05 Dec 2022 14:13
Publisher DOI:	10.1002/prot.24031
PubMed ID:	22275005
Web of Science ID:	000302541900009
URI:	https://boris.unibe.ch/id/eprint/17477 (FactScience: 225257)