Large-Scale Conformational Transitions and Dimerization Are Encoded in the Amino-Acid Sequences of Hsp70 Chaperones

By Duccio Malinverni, Simone Marsili, Alessandro Barducci, Paolo De Los Rios. 2015

61 citations recorded by the source corpus.

Hsp70s are a class of ubiquitous and highly conserved molecular chaperones playing a central role in the regulation of proteostasis in the cell. Hsp70s assist a myriad of cellular processes by binding unfolded or misfolded substrates during a complex biochemical cycle involving large-scale structural rearrangements. Here we show that an analysis of coevolution at the residue level fully captures the characteristic large-scale conformational transitions of this protein family, and predicts an evolutionary conserved–and thus functional–homo-dimeric arrangement. Furthermore, we highlight that the features encoding the Hsp70 dimer are more conserved in bacterial than in eukaryotic sequences, suggesting that the known Hsp70/Hsp110 hetero-dimer is a eukaryotic specialization built on a pre-existing template.

Subfields: Computational Theory and Mathematics, Molecular Biology

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Citations in the corpus

Connecting the Sequence-Space of Bacterial Signaling Proteins to Phenotypes Using Coevolutionary Landscapes (2016, background): “…including repeat proteins (Espada et al. 2015), as well as identify additional functionally relevant conformational states (Morcos et al. 2013; Malinverni et al. 2015; Sutto et al. 2015) and multi-meric states (Schug et al. 2009; Weigt et al. 2009; Morcos et al. 2011; dos Santos et al. 2015;…”
Inter-residue, inter-protein and inter-family coevolution: bridging the scales (2017, methodology): “The dimerization of Hsp70, predicted in [29] using DCA, has been functionally confirmed [41].”
Large-scale identification of coevolution signals across homo-oligomeric protein interfaces by direct coupling analysis (2017, background): “A similar case was reported for Hsp70 chaperones, where supposed crystallographic artifacts were identified as coevolving contacts (41) and subsequently shown to be physiologically relevant (42).”
Learning protein constitutive motifs from sequence data (2018, methodology): “We have constructed amultiple sequence alignment for HSP70 withN = 675 consensus sites and B = 32, 170 sequences, starting from the seeds of Malinverni et al. (2015), and queried SwissProt and Trembl UniprotKB databases using HMMER3 Eddy (2011). Annotated sequences were grouped based on their phylog”