Peeking from behind the veil of enigma: emerging insights on small heat shock protein structure and function

Abstract

This is a short paper on new ways to think about the structure and function of small heat shock proteins (sHSPs), perhaps the most enigmatic family among protein chaperones. The goal is to incorporate new observations regarding the disordered regions of small heat shock proteins (sHSPs) into the large body of structural information on the conserved structural alpha-crystallin domains (ACD) that define the sHSP family. Disordered regions (N-terminal region and C-terminal region or NTR and CTR, respectively) represent over 50% of the sHSP sequence space in the human genome and are refractory to traditional structural biology approaches, posing a roadblock on the path towards a mechanistic understanding of how sHSPs function. A model in which an ACD dimer serves as a template that presents three grooves into which other proteins or other segments of sHSPs can bind is presented. Short segments within the disordered regions are observed to bind into the ACD grooves. There are more binding segments than there are grooves, and each binding event is weak and transient, creating a dynamic equilibrium of tethered and untethered disordered regions. The ability of an NTR to be in dynamic equilibrium between tethered/sequestered and untethered states suggests several mechanistic alternatives that need not be mutually exclusive. New ways of thinking about (and approaching) the intrinsic properties of sHSPs may finally allow the veil of enigma to be removed from sHSPs.

Proteinaceous Transformers: Structural and Functional Variability of Human sHsps

“…The available structures indicate that the key to overall structural flexibility might be envisioned in the variability of the contacts formed by three sequence parts (NTR, ACD, CTR). This is further supported by progress in understanding the structure functional relationship of some other human sHsps ( Figure 3 ) [ 63 , 64 , 66 , 145 ].…”

“…Additionally, a conserved sequence stretch of one of the Hsp20 NTRs (residues 27-RLFDQRFG-34; [ 63 , 90 ]) binds to a groove formed on the ACD dimer (β3/β3), which represents a similar structural arrangement as observed for the NTR-ACD contacts in the HspB2-HspB3 hetero-oligomer [ 64 ]. Interestingly, the two NTRs of pHsp20 display different arrangements, again highlighting the structural flexibility modulating the contacts formed and once more defining the NTR as key player for structural variability ( Figure 3 C) [ 17 , 82 , 145 ]. Several grooves on the ACD additionally provide the necessary, suitable contact sides for the NTR, presumably allowing the variability in oligomer formation [ 64 , 145 ].…”

“…Interestingly, the two NTRs of pHsp20 display different arrangements, again highlighting the structural flexibility modulating the contacts formed and once more defining the NTR as key player for structural variability ( Figure 3 C) [ 17 , 82 , 145 ]. Several grooves on the ACD additionally provide the necessary, suitable contact sides for the NTR, presumably allowing the variability in oligomer formation [ 64 , 145 ].…”

The Heterooligomerization of Human Small Heat Shock Proteins Is Controlled by Conserved Motif Located in the N-Terminal Domain

“…Oversimplifying, we can suppose that HspB1 and HspB5 have three, whereas HspB6 and HspB8 have only two potential sites involved in heterooligomerization. It was suggested that conserved (S/G)RLFD pentapeptide could interact with ACD [41] and by this means drive the interaction of different sHsps. In the case of HspB1 and HspB5, the mutation or deletion of this pentapeptide in either HspB1 or HspB5 will decrease the number of potential binding sites from six (three on HspB1 and three on HspB5) to five.…”

Small Heat Shock Proteins in Cancers: Functions and Therapeutic Potential for Cancer Therapy

“…The ACD is thought to be essential for the dimerization and function of sHSPs [5]. The NTR is generally hydrophobic [6] and involved in oligomer formation of sHSPs and the interaction with substrate proteins [7]. The CTR is polar, flexible, and plays a key role in the stability and assembly of oligomers [8].…”