HSP60: Figures

Figure 1. Structures of prokaryotic GroEL. 

(Top) Schematic representation of apo-GroEL from E. coli. Each monomer is composed of three structural domains: apical (AD; residues 191-376), intermediate (ID) consisting of I1 (residues 134-190) and I2 (377-408), and equatorial (ED) consisting of E1 (residues 6-133) and E2 (residues 409-523). Also, GroEL harbors several highly conserved regions and residues, some of which are given (for details see text). (Bottom) Crystal structures of monomeric (reproduced from Clare and Saibil, 2013 ¹³⁸) and heptameric GroEL (PDB ID: 1OEL) ^{27, 28}. Each GroEL monomer contains crucial helices such as H (red), I (orange), M (green), and D (magenta) ¹³⁸. Helix D within the equatorial domain has been proposed to transmit the nucleotide binding state of one heptameric ring to the other. Helix M within the intermediate domain harbors a catalytic residue (Asp398) which is important for ATP hydrolysis. Helices H and I are implicated in binding of GroES and unfolded polypeptides ¹³⁸.

 

Figure 2. Crystal structure of GroEL and GroES.

Crystal structure of GroEL₁₄-GroES₇-ADP(AIFx)₇ (PDB ID: 1SVT) ⁴²¹, and monomeric GroEL-GroES-ADP(AIF₃) reproduced from Clare and Saibil (2013) ¹³⁸. GroEL and GroES constitute a GroEL₁₄/ADP₇/GroES complex in the presence of Mg²⁺/ATP. However, GroEL can also form a complex with two GroES heptamers as a function of the K⁺ concentration and the ATP/ADP ratio. Single subunits (right) wit nucleotide given in grey contain helix D (magenta), H (red), I (orange), and M (green) fulfilling certain functions ¹³⁸.

 

Figure 3. Conformational changes in GroEL after ATP binding. 

Ribbon and tube representation of apo-GroEL (PDB ID: 1OEL) ^{27, 28}, GroEL-Rs1 (PDB ID: 4AAQ) ¹⁶⁴, GroEL-Rs2 (PDB ID: 4AAR) ¹⁶⁴, GroEL-Rs-open (PDB ID: 4AAS) ¹⁶⁴ and GroEL-GroES-ADP(AIF₃) (PDB ID: 1SVT). The single cartoons show the critical helices H (red), I (orange) and M (green) as well as amino acid residues essential in forming salt bridges between single subunits with negatively charged residues in red, and positive ones in blue, and the contacts are listed for each ring (reproduced from Clare and Saibil ¹³⁸). T, tense allosteric state (unliganded); R, relaxed states (ATP-bound). Rs rings are the ATP-bound rings from GroEL-ATP₇ complexes (single).

 

Figure 4. Cartoon illustrating the GroEL/GroES chaperone folding.

GroEL consists of 14 identical subunits forming two heptameric rings arranged in a barrel-like structure with an inner cavity. In the presence of Mg²⁺/ATP, GroEL and GroES rapidly constitute a GroEL₁₄/ADP₇/GroES complex. GroEL can also form a complex with two GroES heptamers depending on the K⁺ concentration and the ATP/ADP ratio. A polypeptide destined for folding translocates into the folding chamber of one (cis) ring followed by its capping with heptameric GroES. Subsequent folding of the unfolded polypeptide requires the presence of ATP. A further folding process is started in the second (trans) ring after dissociation of GroES and release of ADP and the folded protein.

 

Figure 5. Hsp60-targeting compounds.

These drugs either interact with Hsp60 cysteine residues, or affect Hsp60 ATPase activity, HIF-1α accumulation or Hsp60-mediated cell growth, respectively (for details see text).