Abstract
BackgroundSirtuins genes are widely distributed by evolution and have been found in eubacteria, archaea and eukaryotes. While prokaryotic and archeal species usually have one or two sirtuin homologs, in humans as well as in eukaryotes we found multiple versions and in mammals this family is comprised of seven different homologous proteins being all NAD-dependent de-acylases. 3D structures of human SIRT2, SIRT3, and SIRT5 revealed the overall conformation of the conserved core domain but they were unable to give a structural information about the presence of very flexible and dynamically disordered regions, the role of which is still structurally and functionally unclear. Recently, we modeled the 3D-structure of human SIRT1, the most studied member of this family, that unexpectedly emerged as a member of the intrinsically disordered proteins with its long disordered terminal arms. Despite clear similarities in catalytic cores between the human sirtuins little is known of the general structural characteristics of these proteins. The presence of disorder in human SIRT1 and the propensity of these proteins in promoting molecular interactions make it important to understand the underlying mechanisms of molecular recognition that reasonably should involve terminal segments. The mechanism of recognition, in turn, is a prerequisite for the understanding of any functional activity. Aim of this work is to understand what structural properties are shared among members of this family in humans as well as in other organisms.ResultsWe have studied the distribution of the structural features of N- and C-terminal segments of sirtuins in all known organisms to draw their evolutionary histories by taking into account average length of terminal segments, amino acid composition, intrinsic disorder, presence of charged stretches, presence of putative phosphorylation sites, flexibility, and GC content of genes. Finally, we have carried out a comprehensive analysis of the putative phosphorylation sites in human sirtuins confirming those sites already known experimentally for human SIRT1 and 2 as well as extending their topology to all the family to get feedback of their physiological functions and cellular localization.ConclusionsOur results highlight that the terminal segments of the majority of sirtuins possess a number of structural features and chemical and physical properties that strongly support their involvement in activities of recognition and interaction with other protein molecules. We also suggest how a multisite phosphorylation provides a possible mechanism by which flexible and intrinsically disordered segments of a sirtuin supported by the presence of positively or negatively charged stretches might enhance the strength and specificity of interaction with a particular molecular partner.
Highlights
Sirtuins genes are widely distributed by evolution and have been found in eubacteria, archaea and eukaryotes
In the population of the SIRT1s we find an increase of the N-terminal region lengths during the evolution until to the vertebrata, where these regions remain almost constant while the C-terminal region length is variable in the most ancient organisms and remains constant only in the vertebrata
In the face of this quite typical catalytic activity, they developed a dynamic ability for the recognition of molecular multi-partner, an ability that becomes increasingly complex with increasing metabolic complexity and supported by disordered flexible segments as phospho-isomers
Summary
Sirtuins genes are widely distributed by evolution and have been found in eubacteria, archaea and eukaryotes. While prokaryotic and archeal species usually have one or two sirtuin homologs, in humans as well as in eukaryotes we found multiple versions and in mammals this family is comprised of seven different homologous proteins being all NAD-dependent de-acylases. The presence of disorder in human SIRT1 and the propensity of these proteins in promoting molecular interactions make it important to understand the underlying mechanisms of molecular recognition that reasonably should involve terminal segments. Many studies have determined the cellular location of human SIRT families and their biological functions [4]. SIRT3 is known as a mitochondrial protein, but it seems to act as a nuclear protein transferred into mitochondria during cellular stress [8,9], its functional importance is still controversial [10]. SIRT6 and SIRT7 are nuclear proteins, associated with heterochromatic regions and nucleoli, respectively [13,14]
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