Most proteins need to fold to their correct three-dimensional structure to be functional. Defects in protein folding can lead to aggregation or degradation and are associated with several pathological conditions. This issue of Nature Structural & Molecular Biology contains a Focus on Protein Folding with freely accessible Reviews and Perspectives covering the basic concepts and the latest developments in the field.

Transient receptor potential channels are involved in sensory perception, and TRPV1 is a sensor of burning pain signals and can be modulated by acidic pH, capsaicin and heat. Substituted cysteine accessibility is used to probe state-dependent structural arrangements of the presumed pore-lining S6 helix, revealing two constrictions that participate in gating activity of the channel pore.

Hedgehog (Hh) proteins are involved in multiple developmental processes. Hedgehog-interacting protein (HHIP) binds and inhibits vertebrate Hhs. Structures of HHIP in complex with vertebrate Hhs now show a distinct binding site from previous ligand structures, with the pseudocatalytic site playing a key binding role.

The yeast telomere protein Cdc13 is involved both in capping the telomere and in recruiting telomerase, and can thus switch the telomere between unextendable and extendable states. Now the molecular chaperone Hsp82 is shown to promote the switch to the telomerase extendable state by modulating the DNA-binding activity of Cdc13.