Functional Innovation in the Evolution of the Calcium-Dependent System of the Eukaryotic Endoplasmic Reticulum

Abstract

The origin of eukaryotes was marked by the emergence of several novel subcellular systems. One such is the calcium (Ca 2+)-stores system of the endoplasmic reticulum, which profoundly influences diverse aspects of cellular function including signal transduction, motility, division, and biomineralization. We use comparative genomics and sensitive sequence and structure analyses to investigate the evolution of this system. Our findings reconstruct the core form of the Ca 2+-stores system in the last eukaryotic common ancestor as having at least 15 proteins that constituted a basic system for facilitating both Ca 2+ flux across endomembranes and Ca 2+-dependent signaling. We present evidence that the key EF-hand Ca 2+-binding components had their origins in a likely bacterial symbiont other than the mitochondrial progenitor, whereas the protein phosphatase subunit of the ancestral calcineurin complex was likely inherited from the asgard archaeal progenitor of the stem eukaryote. This further points to the potential origin of the eukaryotes in a Ca 2+-rich biomineralized environment such as stromatolites. We further show that throughout eukaryotic evolution there were several acquisitions from bacteria of key components of the Ca 2+-stores system, even though no prokaryotic lineage possesses a comparable system. Further, using quantitative measures derived from comparative genomics we show that there were several rounds of lineage-specific gene expansions, innovations of novel gene families, and gene losses correlated with biological innovation such as the biomineralized molluscan shells, coccolithophores, and animal motility. The burst of innovation of new genes in animals included the wolframin protein associated with Wolfram syndrome in humans. We show for the first time that it contains previously unidentified Sel1, EF-hand, and OB-fold domains, which might have key roles in its biochemistry.

Bacterial death and TRADD-N domains help define novel apoptosis and immunity mechanisms shared by prokaryotes and metazoans

“…This is exemplified by the fact that arthropods or cephalopod molluscs, which, like vertebrates, tend to be highly motile, have very few (e.g., DEDD2) or no TRADD-N domains. We quantified this tendency using the previously devised metric the polydomain score (PDS) ( Schäffer et al, 2020 ) that captures both the prevalence (tendency to occur as LSEs) and the domain architectural complexity of a class of proteins in a given organism as a single number ( Figure 5E ; see Materials and methods). Whereas the majority of organisms show TRADD-N proteins with comparable PDS, the above-mentioned marine metazoans are dramatic outliers, with significantly higher PDS than the mean of 74 (often orders of magnitude greater; range of 300–9000; p<10 –6 ; Figure 5E ; Supplementary file 5 ).…”

“…This, coupled with inclusive fitness due to their clonal nature or close relatedness, favors the origin of apoptotic mechanisms of defense that limit the invasions to the initially infected cells. Other components of the metazoan toolkit, such as components of the calcium stores system and adhesion molecules, have also been reported to have their roots in bacteria with multicellular tendencies (e.g., cyanobacteria) ( Schäffer et al, 2020 ; Aravind et al, 2003 ). Hence, special habitats that bring together colonial eukaryotes and bacteria (e.g., stromatolites) might have been the epicenters of the origin and spread of multicellularity ( Lyons and Kolter, 2015 ; Schirrmeister et al, 2011 ; Bosak et al, 2013 ).…”

“…Delimited datasets used in these analyses are available in the source data files and at ftp://ftp.ncbi.nih.gov/pub/aravind/Death_TRADDN/ . PDS were computed thus ( Schäffer et al, 2020 ): organism PDS were calculated as follows: if counts the number of proteins of a given protein domain in an organism , is the set of all proteins studied, and is the set of all organisms studied, then the PDS for an organism is defined as …”

Origins of eukaryotic excitability

“…Comparative genomics indicates much of this diversity evolved during eukaryogenesis in stem eukaryotes and was present in the LECA (e.g. [ 184 ]).…”

“…The core Ca 2+ transport systems of ER and plasma membrane channels and pumps have homologues across diverse eukaryotes and were likely present in the LECA. These include SERCA, PMCA, InsP3R, trimeric intracellular cation-specific channels (TRIC) and ORAI [ 184 , 189 , 190 ]. However, some of the machinery of calcium signalling evolved in the common ancestor of Apusozoa, animals and fungi, representing a post-LECA diversification of ionic signalling (e.g.…”