Sequence Divergence and Functional Specializations of the Ancient Spliceosomal SF3b: Implications in Flexibility and Adaptations of the Multi-Protein Complex

Abstract

Multi-protein assemblies are complex molecular systems that perform highly sophisticated biochemical functions in an orchestrated manner. They are subject to changes that are governed by the evolution of individual components. We performed a comparative analysis of the ancient and functionally conserved spliceosomal SF3b complex, to recognize molecular signatures that contribute to sequence divergence and functional specializations. For this, we recognized homologous sequences of individual SF3b proteins distributed across 10 supergroups of eukaryotes and identified all seven protein components of the complex in 578 eukaryotic species. Using sequence and structural analysis, we establish that proteins occurring on the surface of the SF3b complex harbor more sequence variation than the proteins that lie in the core. Further, we show through protein interface conservation patterns that the extent of conservation varies considerably between interacting partners. When we analyze phylogenetic distributions of individual components of the complex, we find that protein partners that are known to form independent subcomplexes are observed to share similar profiles, reaffirming the link between differential conservation of interface regions and their inter-dependence. When we extend our analysis to individual protein components of the complex, we find taxa-specific variability in molecular signatures of the proteins. These trends are discussed in the context of proline-rich motifs of SF3b4, functional and drug binding sites of SF3b1. Further, we report key protein-protein interactions between SF3b1 and SF3b6 whose presence is observed to be lineage-specific across eukaryotes. Together, our studies show the association of protein location within the complex and subcomplex formation patterns with the sequence conservation of SF3b proteins. In addition, our study underscores evolutionarily flexible elements that appear to confer adaptive features in individual components of the multi-protein SF3b complexes and may contribute to its functional adaptability.

Srinivasan (1962–2021) in Bioinformatics and beyond

“…In collaboration with multiple laboratories, Srini’s group studied fascinating biological systems, including protein assemblies of ribosomes and spliceosomes ( Bhat et al , 2015 ; Pudi et al , 2003 ; Yazhini et al , 2022 ) and developed powerful computational tools for studying structures of large assemblies derived from cryo-electron microscopy ( Joseph et al , 2016 ; Rakesh et al , 2016 ). As is true of several structural bioinformaticians, his group relied on publicly available structural data and were concerned with the quality of protein–ligand data, deposited through X-ray or cryo-EM studies ( Chakraborti et al , 2021 ).…”