The entropic force generated by intrinsically disordered segments tunes protein function

Abstract

Protein structures are dynamic and can explore a large conformational landscape1,2. Only some of these structural substates are important for protein function (i.e. ligand binding, catalysis and regulation)3–5. How evolution shapes the structural ensemble to optimize a specific function is poorly understood>3,4. One of the constraints on the evolution of proteins is the stability of the folded ‘native’ state. Despite this, 44% of the human proteome contains intrinsically disordered (ID) peptide segments >30 residues in length6, the majority of which have no known function7–9. Here we show that the entropic force produced by an ID carboxy-terminus (ID-tail) shifts the conformational ensemble of human UDP-α-D-glucose-6-dehydrogenase (hUGDH) toward a substate with a high affinity for an allosteric inhibitor. The function of the ID-tail does not depend on its sequence or chemical composition. Instead, the affinity enhancement can be accurately predicted based on the length of the ID segment and is consistent with the entropic force generated by an unstructured peptide attached to the protein surface10–13. Our data show that the unfolded state of the ID-tail rectifies the dynamics and structure of hUGDH to favor inhibitor binding. Because this entropic rectifier does not have any sequence or structural constraints, it is an easily acquired adaptation. This model implies that evolution selects for disordered segments to tune the energy landscape of proteins, which may explain the persistence of ID in the proteome.

The molecular mechanism of Hsp90-induced oligomerization of Tau

“…Indeed, Tau fragments lacking the N-terminal region, and therefore exposing the aggregation prone repeat region, feature drastically accelerated aggregation rates, such as Tau-RD (45). Remarkably, Tau-RD is less soluble than the full-length protein despite having a higher net charge (pI 9.67 for Tau-RD vs. 8.24 for full-length) (45,46). Hsp90 binds to Tau-RD, consistent with previous findings by us (25).…”

Omnipresent Maxwell's demons orchestrate information management in living cells

“…In bacteria, it is made of three long transcript precursors that are folded and matured into 16S RNA, 23S RNA and 5S RNA molecules. These molecules further interact with ribosomal proteins that act as scaffolds and consolidating agents, based on a lock-and-key type of interaction, complemented with local entropy-driven folding of disordered or flexible regions (Keul et al, 2018). As in enzyme catalysis, where substrates must meet an enzyme to allow it to perform a catalysed reaction, this process is essentially driven by diffusion.…”

PTBP2-dependent alternative splicing regulates protein transport and mitochondria morphology in post-meiotic germ cells.

“…Interestingly, exons spliced in a tissue-restricted manner frequently encode intrinsically disordered regions (IDRs), linear peptide motifs, and post-translational modification sites. These have been proposed to tune protein function, and rewire protein-protein interaction networks and signaling pathways (Merkin et al, 2012;Buljan et al, 2012;Ellis et al, 2012;Keul et al, 2018). While it is known that nearly all multi-exon protein coding genes in mice and humans generate multiple AS mRNA isoforms (Barbosa-Morais et al, 2012;Merkin et al, 2012), our understanding of how networks of AS isoforms are coordinately regulated to alter cellular properties remains limited.…”