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Roco Proteins and the Parkinson's Disease-Associated LRRK2

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Roco Proteins and the Parkinson's Disease-Associated LRRK2 International Journal of Molecular Sciences Review Roco Proteins and the Parkinson’s Disease-Associated LRRK2 Jingling Liao 1,2,* and Quyen Q. Hoang 2,3,4,* 1 Department of Public Health, Wuhan University of Science and Technology School of Medicine, Wuhan 430081, China 2 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA 3 Department of Neurology, Indiana University School of Medicine, Indianapolis, IN 46202, USA 4 Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA * Correspondence: [email protected] (J.L.); [email protected] (Q.Q.H.); Tel.: +86-177-8646-6520 (J.L.); +1-317-274-4371 (Q.Q.H.) Received: 15 November 2018; Accepted: 14 December 2018; Published: 17 December 2018 Abstract: Small G-proteins are structurally-conserved modules that function as molecular on-off switches. They function in many different cellular processes with differential specificity determined by the unique effector-binding surfaces, which undergo conformational changes during the switching action. These switches are typically standalone monomeric modules that form transient heterodimers with specific effector proteins in the ‘on’ state, and cycle to back to the monomeric conformation in the ‘off’ state. A new class of small G-proteins called “Roco” was discovered about a decade ago; this class is distinct from the typical G-proteins in several intriguing ways. Their switch module resides within a polypeptide chain of a large multi-domain protein, always adjacent to a unique domain called COR, and its effector kinase often resides within the same polypeptide. As such, the mechanisms of action of the Roco G-proteins are likely to differ from those of the typical G-proteins. Understanding these mechanisms is important because aberrant activity in the human Roco protein LRRK2 is associated with the pathogenesis of Parkinson’s disease. This review provides an update on the current state of our understanding of the Roco G-proteins and the prospects of targeting them for therapeutic purposes. Keywords: Roc; Intramolecular mechanism; Small GTPase; LRRK2 1. Introduction The Ras/GTPase superfamily consists of monomeric small GTPases with molecular masses of 20–30 kDa. Small GTPases act as molecular switches that cycle between the active GTP-bound and inactive GDP-bound states. The functional cycle is regulated mainly by two different groups of regulatory proteins: (1) The Guanine nucleotide exchange factors (GEFs), which facilitate GDP dissociation from the small GTPases and exchanging with GTP leading to the transmission of various upstream signals; and (2) GTPase-activating proteins (GAPs), which accelerate the speed of the intrinsic GTP hydrolysis of the GTPase, thereby resulting in the inactivation of the molecular switch. The Ras/GTPase superfamily perform their cellular function by activating downstream protein kinase cascades. The Ras signaling pathway is a classic example in the mitogen-activated protein kinase (MAPK) pathway. In the past decade, a novel group of Ras/GTPase superfamily has been discovered, which is called the Ras of complex proteins (Roc). These Roc GTPase exist as a domain within a large multi-domain protein [1]. Roc was first described in the slim mold Dictyostelium discoideum which Int. J. Mol. Sci. 2018, 19, 4074; doi:10.3390/ijms19124074 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2018, 19, 4074 2 of 15 Int. J. Mol. Sci. 2018, 19, x 2 of 15 possesses a complex protein termed GbpC (cGMP binding protein C) [2]. P.J.M. Van Haastert’s andgroup J.L. identified Smith’s group that GbpC identified contains that a GbpCnumber contains of different a number domains, of different including domains, a leucine-rich including repeats a leucine-richdomain (LRR), repeats a Rasdomain domain, (LRR) MEK, a Raskinase domain, domain, MEK a Ras kinase guanine domain, nucleotide a Ras guanine exchange nucleotide factor N- exchangeterminal factor(RasGEF-N) N-terminal domain, (RasGEF-N) a DEP domain, domain, a aRa DEPsGEF domain, domain, a RasGEFa cGMP-binding domain, domain, a cGMP-binding a GRAM domain,domain a (Glucosyltransferases GRAM domain (Glucosyltransferases Rab-like GTPase Rab-like activators GTPase and Myotubularins), activators and Myotubularins), and a second cGMP- and a secondbinding cGMP-binding domain. In domain.this study, In this the study, authors the authors proposed proposed that thatthe theMEKK MEKK activity activity of of GbpCGbpC isis intramolecularlyintramolecularly regulated regulated by by its upstreamits upstream Ras domain,Ras domain, and that and the that MEKK the activityMEKK ofactivity GbpC dependsof GbpC ondepends the cGMP on the transmitted cGMP transmitted from the cGMP-binding from the cGMP domains-binding through domains the through RasGEF the and RasGEF Ras domains, and Ras alldomains, occurring all within occurring the samewithin protein the same (Figure protein1). This(Figure Ras 1). domain This Ras is unique domain with is unique respect with to the respect other to canonicalthe other Ras-family canonical GTPases,Ras-family in thatGTPases, both itsin upstreamthat bothregulator its upstream and itsregulator downstream and its effector downstream kinase areeffector contained kinase within are contained the same within polypeptide the same chain. polypeptide chain. FigureFigure 1. 1.Schematic Schematic depictiondepiction of the the Roco Roco proteins. proteins. AA common common feature feature among among them them is the is thecentral central Roc- Roc-CORCOR domains, domains, which which are flanked are flanked by various by various function functionalal domains. domains. Ank, ankyrin Ank, ankyrin domain; domain; LRR, leucine- LRR, leucine-richrich repeats; repeats; ROC, Ras ROC, of Rascomplex of complex proteins; proteins; COR, C-terminal COR, C-terminal of Roc; of Kinase, Roc; Kinase, kinase kinasedomain; domain; WD40, WD40,WD40-like WD40-like beta-propeller beta-propeller repeat repeatdomain; domain; cNB, cyclic cNB, nucleotide cyclic nucleotide binding; binding; DEP, Dishevelled, DEP, Dishevelled, EGL-10, EGL-10,pleckstrin pleckstrin domain; domain; GEF, guanine GEF, guanine nucleotide nucleotide exchange exchange factor; GRAM, factor; GRAM,glucosyltransferases, glucosyltransferases, Rab-like Rab-likeGTPase GTPaseactivators activators and myotubularins and myotubularins domain; domain; Death, Death, death death domain; domain; PTP, PTP, proteinprotein tyrosinetyrosine phosphatasephosphatase domain; domain; RhoGEF/RhoGAP, RhoGEF/RhoGAP, RhoGEF/GAP RhoGEF/GAP domain.domain. TheThe redred dotted-lines dotted-lines highlight highlight the the featuresfeatures that that differentiate differentiate the the three three groups groups of of Roco Roco proteins. proteins. Additionally,Additionally, P.J.M. P.J.M. Van Van Haastert’s Haastert’s group group discovered discovered the the region region between between the the Roc Roc and and the the kinase kinase domaindomain COR COR (C-terminus (C-terminus ofof Roc), and called called proteins proteins consisting consisting of of Roc Roc and and COR COR “Roco “Roco proteins” proteins” for fortheir their unique unique structures structures [1]. [1]. The The group group used used the the amino acid sequencesequence encompassingencompassing thethe Roc-COR Roc-COR tandemtandem domain domain of of GbpC GbpC to to search search for for other other Roco Roco proteins proteins from from various various databases. databases. They They found found Roco Roco proteinsproteins in in prokaryotes, prokaryotes,Dictyostelium Dictyostelium, plants,, plants, and and animals, animals, each each consisting consisting of a juxtapositionof a juxtaposition of the of Roc the andRoc the and COR the domains;COR domains; there are there no proteinsare no proteins containing containing either Roc either or COR Roc domainor COR alone.domain Based alone. on Based their domainon their architecture, domain architecture, the identified the Roco identified proteins Roco are categorizedproteins are into categorized three groups. into Thethree largest groups. group The islargest found group in Dictyostelium is found inand Dictyostelium metazoan, and which metazoan, is characterized which is bycharacterized the central by LRR-Roc-COR-Kinase the central LRR-Roc- tandemCOR-Kinase domains tandem (Figure domains1). In these (Figure proteins, 1). In these the central proteins, architecture the central comprises architecture the Roc-CORcomprises tandem the Roc- domains,COR tandem which domains, are always which preceded are byalways a leucine-rich preceded repeat by a domainleucine-rich (LRR) repeat and followed domain by (LRR) a kinase and domainfollowed belonging by a kinase to the domain MAPKKK belonging subfamily. to the The MAPKKK N- and subfamily. C-terminus The flanking N- and the C-terminus Roc-COR domainflanking consiststhe Roc-COR of remarkably domain consists diverse of structures, remarkably including diverseWD-40-like structures, including beta-propeller WD-40-like repeats beta-propeller (WD40 and Kelchrepeats motif), (WD40 and and domains Kelch motif), which and interact domains with which small GTPasesinteract with (RasGEF, small RhoGEF,GTPases and(RasGEF, RhoGAP) RhoGEF, [1] (Figureand RhoGAP)1). The second [1] (Figure group 1). of RocoThe second proteins group is characterized of Roco proteins by lacking is characte of the kinaserized domainby lacking is found of the inkinase mammals domain (MASL1), is found the in plantmammals Arabidopsis, (MASL1), and the prokaryotes plant
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