The collapse of polypeptides is thought important to protein folding, aggregation, intrinsic disorder, and phase separation. However, whether polypeptide collapse is modulated in cells to control protein states is unclear. Here, using integrated protein manipulation and imaging, we show that the chaperonin GroEL-ES can accelerate the folding of proteins by strengthening their collapse. GroEL induces contractile forces in substrate chains, which draws them into the cavity and triggers a general compaction and discrete folding transitions, even for slow-folding proteins. This collapse enhancement is strongest in the nucleotide-bound states of GroEL and is aided by GroES binding to the cavity rim and by the amphiphilic C-terminal tails at the cavity bottom. Collapse modulation is distinct from other proposed GroEL-ES folding acceleration mechanisms, including steric confinement and misfold unfolding. Given the prevalence of collapse throughout the proteome, we conjecture that collapse modulation is more generally relevant within the protein quality control machinery.

Molecular catch bonds are ubiquitous in biology and well-studied in the context of leukocyte extravasion 1 , cellular mechanosensing 2,3 , and urinary tract infection 4 . Unlike normal (slip) bonds, catch bonds strengthen under tension.The current paradigm is that this remarkable ability enables cells to increase their adhesion in fast fluid flows 1,4 , and hence provides 'strength-on-demand'.Recently, cytoskeletal crosslinkers have been discovered that also display catch bonding [5][6][7][8] . It has been suggested that they strengthen cells, following the strength-on-demand paradigm 9,10 . However, catch bonds tend to be weaker compared to regular (slip) bonds because they have cryptic binding sites that are often inactive [11][12][13] . Therefore, the role of catch bonding in the cytoskeleton remains unclear. Here we reconstitute cytoskeletal actin networks to show that catch bonds render them both stronger and more deformable than slip bonds, even though the bonds themselves are weaker. We develop a model to show that weak binding allows the catch bonds to mitigate crack initiation by moving from low-to high-tension areas in response to mechanical loading. By contrast, slip bonds remain trapped in stress-free areas. We therefore propose that the mechanism of catch bonding is typified by dissociation-on-demand rather than strength-on-demand. Dissociation-on-demand can explain how both cytolinkers [5][6][7][8]10,14,15 and adhesins 1,2,4,12,[16][17][18][19][20] exploit continuous redistribution to combine mechanical strength with the adaptability required for movement and proliferation 21 . Our findings provide a mechanistic understanding of diseases where catch bonding is compromised 11,12 such as kidney focal segmental glomerulosclerosis 22,23 , caused by the α-actinin-4 mutant studied here. Moreover, catch bonds provide a route towards creating life-like materials that combine strength with deformability 24 .Here we exploit the actin-binding protein α-actinin-4 and its K225E point mutant, associated with the heritable disease kidney focal segmental glomerulosclerosis type 1 22,25 , to identify the role of catch bonds in the mechanical properties of actin networks. Actin networks are key determinants of cell mechanics, together with other cytoskeletal proteins. To isolate the role of catch bonds in actin mechanics, we reconstitute actin networks from purified components. We first characterized the binding affinity of the two protein variants for actin .

Molecular catch bonds are ubiquitous in biology and well-studied in the context of leukocyte extravasion1, cellular mechanosensing2,3, and urinary tract infection4. Unlike normal (slip) bonds, catch bonds strengthen under tension. The current paradigm is that this remarkable ability enables cells to increase their adhesion in fast fluid flows1,4, and hence provides ‘strength-on-demand’. Recently, cytoskeletal crosslinkers have been discovered that also display catch bonding5–8. It has been suggested that they strengthen cells, following the strength-on-demand paradigm9,10. However, catch bonds tend to be weaker compared to regular (slip) bonds because they have cryptic binding sites that are often inactive11–13. Therefore, the role of catch bonding in the cytoskeleton remains unclear. Here we reconstitute cytoskeletal actin networks to show that catch bonds render them both stronger and more deformable than slip bonds, even though the bonds themselves are weaker. We develop a model to show that weak binding allows the catch bonds to mitigate crack initiation by moving from low- to high-tension areas in response to mechanical loading. By contrast, slip bonds remain trapped in stress-free areas. We therefore propose that the mechanism of catch bonding is typified by dissociation-on-demand rather than strength-on-demand. Dissociation-on-demand can explain how both cytolinkers5–8,10,14,15 and adhesins1,2,4,12,16–20 exploit continuous redistribution to combine mechanical strength with the adaptability required for movement and proliferation21. Our findings provide a mechanistic understanding of diseases where catch bonding is compromised11,12 such as kidney focal segmental glomerulosclerosis22,23, caused by the α-actinin-4 mutant studied here. Moreover, catch bonds provide a route towards creating life-like materials that combine strength with deformability24.