Rewards of divergence in sequences, 3-D structures and dynamics of yeast and human spliceosome SF3b complexes

Yazhini, A and Sandhya, S and Srinivasan, N (2021) Rewards of divergence in sequences, 3-D structures and dynamics of yeast and human spliceosome SF3b complexes. In: Current Research in Structural Biology, 3 . pp. 133-145.

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Abstract

The evolution of homologous and functionally equivalent multiprotein assemblies is intriguing considering sequence divergence of constituent proteins. Here, we studied the implications of protein sequence divergence on the structure, dynamics and function of homologous yeast and human SF3b spliceosomal subcomplexes. Human and yeast SF3b comprise of 7 and 6 proteins respectively, with all yeast proteins homologous to their human counterparts at moderate sequence identity. SF3b6, an additional component in the human SF3b, interacts with the N-terminal extension of SF3b1 while the yeast homologue Hsh155 lacks the equivalent region. Through detailed homology studies, we show that SF3b6 is absent not only in yeast but in multiple lineages of eukaryotes implying that it is critical in specific organisms. We probed for the potential role of SF3b6 in the spliceosome assembled form through structural and flexibility analyses. By analysing normal modes derived from anisotropic network models of SF3b1, we demonstrate that when SF3b1 is bound to SF3b6, similarities in the magnitude of residue motions (0.86) and inter-residue correlated motions (0.94) with Hsh155 are significantly higher than when SF3b1 is considered in isolation (0.21 and 0.89 respectively). We observed that SF3b6 promotes functionally relevant �open-to-close� transition in SF3b1 by enhancing concerted residue motions. Such motions are found to occur in the Hsh155 without SF3b6. The presence of SF3b6 influences motions of 16 residues that interact with U2 snRNA/branchpoint duplex and supports the participation of its interface residues in long-range communication in the SF3b1. These results advocate that SF3b6 potentially acts as an allosteric regulator of SF3b1 for BPS selection and might play a role in alternative splicing. Furthermore, we observe variability in the relative orientation of SF3b4 and in the local structure of three β-propeller domains of SF3b3 with reference to their yeast counterparts. Such differences influence the inter-protein interactions of SF3b between these two organisms. Together, our findings highlight features of SF3b evolution and suggests that the human SF3b may have evolved sophisticated mechanisms to fine tune its molecular function. © 2021 The Authors

Item Type:	Journal Article
Publication:	Current Research in Structural Biology
Publisher:	Elsevier B.V.
Additional Information:	The copyright for this article belongs to the Author.
Keywords:	binding protein; fungal protein; fusion protein; Hsh155 protein; SF3b complex; SF3b1 protein; SF3b6 protein; small nuclear RNA; unclassified drug, allosterism; amino acid sequence; anisotropic network model; Article; beta chain; computer model; controlled study; cryoelectron microscopy; dynamics; eukaryote; human; molecular evolution; nonhuman; protein binding; protein domain; protein dynamics; protein function; protein protein interaction; protein sequence divergence; protein structure; sequence homology; spliceosome; yeast
Department/Centre:	Division of Biological Sciences > Molecular Biophysics Unit
Date Deposited:	07 Jan 2022 10:40
Last Modified:	07 Jan 2022 10:40
URI:	http://eprints.iisc.ac.in/id/eprint/70942

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