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Genealogy of an ancient protein family: the Sirtuins, a family of disordered members - PubMed

  • ️Tue Jan 01 2013

Genealogy of an ancient protein family: the Sirtuins, a family of disordered members

Susan Costantini et al. BMC Evol Biol. 2013.

Abstract

Background: 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. 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.

Results: We 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.

Conclusions: Our 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.

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Figures

Figure 1
Figure 1

Mean length of the three regions in the family of sirtuins. Bars for N-terminal, catalytic core and C-terminal regions are reported in Red, Green and blue, respectively.

Figure 2
Figure 2

Analysis of charged residue presence. We report the average percentages of charged residues in sirtuin families. Bars for N-terminal, catalytic core and C-terminal regions are reported in Red, Green and blue, respectively.

Figure 3
Figure 3

Results of disordered predictions. We report the percentage of predicted disordered regions in sirtuins. Bars for N-terminal, catalytic core and C-terminal regions are reported in Red, Green and blue, respectively.

Figure 4
Figure 4

GC content trends. We report the trends in the sirtuin family from evolutionary lower organisms to higher and their slopes (black) according to their N-terminal, C-terminal and Core basis content. We have numbered the various organisms according to the sequence shown in Table 1. The colors used for each sirtuin family are reported in the legend.

Figure 5
Figure 5

Chromosomal Data. We report low (400-band; ideogram A) and high (850-band; ideogram B-C) resolution bands of human chromosome 10, 19, 11, 12, 6 and 11. The correspondence between low- and high resolution bands is unequivocally established in the literature (see Materials and methods). Panel b is the ideogram of Francke (1994). In the high-resolution bands of c, dark blue and light blue bands correspond to L1+ and L1− G bands, red and yellow bands to H3+ and H3− R bands, respectively. With rectangle in blu or in red are identified the chromosomal bands in which the sirtuin genes are localized. In the central blue rectangle the GC% of sirtuin genes are reported.

Figure 6
Figure 6

Phylogenetic analysis. We report the trees obtained for full-length sirtuin sequences (A), N-terminal (B) and C- terminal (C) regions with bootstrap values evaluated by SplitsTree 4.

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