Abstract
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.
Highlights
Molecular chaperones are a broad class of proteins that protect cells against the potentially deleterious effects of denatured and unfolded proteins
Direct Coupling Analysis (DCA) was performed on the multiple sequence alignment (MSA) using the Pseudo-Likelihood method ([52,57], see Material and Methods) and predicted contacts were ranked according to their DCA scores, which denote coevolution strength between pairs of residues
DCA predictions can be compared with the structural information available for E. coli DnaK, for which high-resolution structures are available for both ATP- (PDB ID 4jne [22] and 4b9q [21]) and ADP-bound states (PDB ID 2kho [20])
Summary
Starting from the PFAM seed of the Hsp family (PF00012), we manually curated it by adding sequences and suppressing gapped positions. The added sequences were chosen to cover a wide range of organisms, stemming from different taxonomy (see S3 Table). The aligned seed was used to build a Hidden Markov Model (HMM) of the family, using the HMMER utility hmmerbuild. The multiple sequence alignment (MSA) was built by running a HMMER search on the Uniprot database. We used the union of the Uniprot Tremble (un-annotated sequences) and Swissprot (annotated) databases for the extraction of the Hsp MSA. All utilities were run with default parameters. Our Hsp family MSA is available online as supplementary material (S1 Dataset)
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