Dynamics, flexibility, and allostery in molecular chaperonins

Abstract

a b s t r a c tThe chaperonins are a family of molecular chaperones present in all three kingdoms of life. They are classified into Group I and Group II. Group I consists of the bacterial variants (GroEL) and the eukaryotic ones from mitochondria and chloroplasts (Hsp60), while Group II consists of the archaeal (thermosomes) and eukaryotic cytosolic variants (CCT or TRiC). Both groups assemble into a dual ring structure, with each ring providing a protective folding chamber for nascent and denatured proteins. Their functional cycle is powered by ATP binding and hydrolysis, which drives a series of structural rearrangements that enable encapsulation and subsequent release of the substrate protein.Chaperonins have elaborate allosteric mechanisms to regulate their functional cycle. Long-range negative cooperativity between the two rings ensures alternation of the folding chambers. Positive intra-ring cooperativity, which facilitates concerted conformational transitions within the protein subunits of one ring, has only been demonstrated for Group I chaperonins. In this review, we describe our present understanding of the underlying mechanisms and the structurefunction relationships in these complex protein systems with a particular focus on the structural dynamics, allostery, and associated conformational rearrangements.

Dynamic Complexes in the Chaperonin-Mediated Protein Folding Cycle

“…The answer to this question comes from numerous kinetic and mechanistic studies (for a review see Skjærven et al, 2015; Taguchi, 2015) that enable us to peek into what is really happening in order to identify shorter-lived complexes. To simplify the arguments, we will focus on events that occur in the presence of unfolded substrate protein.…”

The chaperonin CCT inhibits assembly of α-synuclein amyloid fibrils by a specific, conformation-dependent interaction

“…Like most chaperonins, CCT is built of two back-to-back rings, each formed by eight different, homologous subunits8. Each subunit is constituted of three domains; the equatorial domain hosts the ATP-binding site and most intra- and inter-ring contacts, the apical domain hosts the substrate binding sites, and the intermediate domain acts as a link between these two domains and transmits signals generated in the equatorial domain to the apical domain after ATP binding and hydrolysis9.…”

Differential conformational modulations of MreB folding upon interactions with GroEL/ES and TRiC chaperonin components

“…The equivalent to GroEL/GroES complex in eukaryotes is the tail-less complex polypeptide 1 ring complex TRiC chaperonin (TCP-1 Ring Complex, also called CCT for chaperonin containing TCP-1). Although the TRiC and GroEL/ES systems share many similarities and have received a lot of attention, there are still fundamental open questions and controversies about their mechanisms of action and substrate recognition12.…”