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Plasma membrane (PM) transporters of the major facilitator superfamily (MFS) are essential for cell metabolism and growth, as well as for survival in response to stress or cytotoxic drugs, in both prokaryotes and eukaryotes. In the yeast Saccharomyces cerevisiae, Jen1 is a monocarboxylate/H+ symporter that has been used to dissect the molecular details underlying control of cellular expression, transport mechanism and turnover of MFS transporters. Here, we present evidence supporting previously non-described roles of the cytosolic N- and C- termini in Jen1 biogenesis, PM stability and activity, through functional analyses of rationally designed truncations and chimeric constructs with UapA, a S. cerevisiae endocytosis-insensitive purine transporter from Aspergillus nidulans. Our results reveal a cryptic role of the N-terminal region and thus show that both cytosolic N- and C-termini are critical for Jen1 trafficking to the PM, transport activity and endocytosis. In particular, we provide evidence that the N- and the C-cytosolic termini of Jen1 undergo transport-dependent dynamic intra-molecular interactions, which critically affect the mechanism of transport and turnover of Jen1. Our results support an emerging concept where the cytosolic tails of PM transporters control transporter expression and function, through flexible intra-molecular interactions with each other and the transmembrane core of the protein. This idea may be extended to other MFS members providing a deeper understanding of conserved, but also evolving, mechanisms underlying MFS transporter structure-function relationships.

IntroductionDepression is characterized by a feeling of deep sadness associated with physiological and cognitive symptoms [1]. Both the ICD-10 and the American Psychiatric Association in their statistical manual of mental illness (DSM-V) characterize depression as a set of symptoms that include depressed mood (sadness, hopelessness), loss of interest and pleasure for previously satisfactory activities, and decreased energy, leading to a significant lack of enthusiasm that interferes with the life of the individual [2,3]. However, in relation to the etiology, most of the scientific community shares the idea that depression has multifactorial causes [4] that can originate from endogenous (neurobiological, genetic) [5], exogenous (psychosocial) [6] or traumatic factors (shock, letdown or a tumor) [7]. A biochemical alteration in the brain caused by a deficiency of serotonin [8], especially in the synaptic cleft, is implicated in the psychogenesis of neurobiological nature, possibly causing an imbalance of both mood and sense of well-being in the individual.This study focuses on problems of attention due to the possibility of accidents. Even though there are several theories related to the functioning of attention in the literature, Mateer & Mapou proposed a model that integrates all the previously proposed theories [9]. They established that attention is divided into two cognitive factors: AbstractIntroduction: Among the symptoms of depression, impairment in the level of attention has been a concern because of the risk of accidents.

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