# Roco Proteins: GTPases with a Baroque Structure and Mechanism
## 1 Introduction  
Parkinson's disease (PD) is the second most common neurological disorder after Alzheimer's disease. 0.3%of the population worldwide suffers from the disease, with an increasing incidence with age [1]. PD is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta combined with the formation of Lewy bodies (fibrillar protein aggregates rich in \(\alpha\)-synuclein) [1, 2]. So far, there are no good clinical biomarkers for PD available, and diagnosis is primarily based on clinical symptoms. These symptoms include bradykinesia or slowness of movement, resting tremor, rigidity of the muscles, and postural imbalance [3]. Today PD still cannot be cured or halted, and only symptom improvement can be provided by medication. Almost all available medication focuses on the substitution or increase of dopamine in the brain, with the dopamine precursor levodopa still being the most commonly used PD medication [4, 5].  
The majority of PD cases are considered to be sporadic or idiopathic [6, 7, 8]. However, the environmental risk factors for PD are not well known or understood. Nevertheless, several environmental factors, such as pesticide and herbicide exposure, have been positively identified as risk factors for the disease [3, 6, 9, 10]. On the other hand, caffeine consumption was shown to decrease the risk for PD [6, 9]. A possible link with a variety of other causative agents like dietary habits, oestrogens, and iron exposure, is still unresolved [3, 6]. The less common familial form of PD is caused by autosomal dominant and recessive gene mutations [7]. To date, 23 genes or loci have been associated with familial PD, of which mutations in the gene coding for leucine-rich repeat kinase 2 (LRRK2) are among the most frequent causes [11, 12, 13]. Moreover, some mutations in LRRK2 havebeen identified as a risk factor for sporadic PD [7]. Importantly, a recent study by [PERSON] et al., showed that LRRK2 kinase activity was enhanced in postmortem brain tissue from patients with idiopathic PD, suggesting that independent of mutations, wild-type LRRK2 plays a role in PD [14]. Therefore, unravelling the working mechanism of LRRK2 can provide significant insights into the pathways leading to neurodegeneration in this disease. LRRK2 is a very large multi-domain protein harboring both GTP hydrolyzing (GTPase) and kinase activity. The protein belongs to a wider family of GTPases, called the Roco protein family, characterized by a central Roc (Ras of complex proteins) and COR (C-terminal of Roc) domain tandem. The Roco protein family was initially described in 2003, and although other family members had been previously investigated, it was only after mutations in LRRK2 were linked to PD that the protein family raised general interest [15].  
This review consists of two parts. First, an overview is given of the wide evolutionary range of Roco proteins, leading to their variety in known physiological functions. In the second part, the focus is shifted towards the GTPase function of the central RocCOR domain tandem of Roco proteins. There is an ongoing debate concerning the working mechanism of the RocCOR module. We have already discussed this topic in detail in a previous review [16]. However, here we take into account important recent findings. Based on these new biochemical, biophysical, and structural data, especially on the Roco monomer-dimer equilibrium, we propose a new working hypothesis for the mechanism of Roco proteins in general, and LRRK2 in particular [17; 18; 19; 20]. For more detailed information concerning the structure and function of the kinase and other domains of LRRK2, we refer to other papers and reviews covering these topics [21; 22; 23; 24].