Is the lipochaperone activity of sHSP a key to the stress response encoded in its primary sequence?

Abstract

Several strategies have been put in place by organisms to adapt to their environment. One of these strategies is the production of stress proteins such as sHSPs, which have been widely described over the last 30 years for their role as molecular chaperones. Some sHSPs have, in addition, the particularity to exert a lipochaperone role by interacting with membrane lipids to maintain an optimal membrane fluidity. However, the mechanisms involved in this sHSP-lipid interaction remain poorly understood and described rather sporadically in the literature. This review gathers the information concerning the structure and function of these proteins available in the literature in order to highlight the mechanism involved in this interaction. In addition, analysis of primary sequence data of sHSPs available in database shows that sHSPs can interact with lipids via certain amino acid residues present on some β sheets of these proteins. These residues could have a key role in the structure and/or oligomerization dynamics of sHPSs, which is certainly essential for interaction with membrane lipids and consequently for maintaining optimal cell membrane fluidity.

Keywords: Lipochaperone activity; Protein structure; Small heat shock protein; Stress response.

Fig. 1

Predicted structure of model A metazoan sHSP (alphafold2 HSPB9 of H. sapiens) and B bacterial sHSP (alphafold2 sHSP of M. jannaschii). The numbers correspond to the sheets allowing interactions between the sHSP. The amino acid sequences SRLFQxFG and IXI correspond to highly conserved sequences in the N- and C-terminal domain in bacteria

Fig. 2

Oligomerization process of sHSP using the example of M. marinum sHSP (pdb 5ZUL) (Bhandari et al. 2019). A Dimerization: interaction between the β6 strand (green) of a monomer with the β2 strand of the adjacent monomer (blue). B Oligomerization: interaction between the C-ter domain of a dimer (red) with the hydrophobic groove formed by the β4 (turquoise) and β8 (orange) strands of an adjacent dimer. C Large oligomer formation: interaction between the free C-ter domain (pink) of the oligomer with the β9 (red) strand on another oligomer

Fig. 3

Mechanism of interaction described between sHSP and the membrane. (1) Dissociation of the sHSP oligomer near the membrane allows lipid-protein interaction. (2) Interaction with the polar head of phospholipids according to their structure and state of fluidization (Tsvetkova et al. ; Maitre et al. 2012). (3) Electrostatic force, occurring during the disassembly process, can attract the protein to the membrane and enhance hydrophobic force. This electrostatic force may expose hydrophobic domains of sHSP leading to protein structure modification (Zhang et al. 2005) which can then bind to the membrane (Chen et al. ; Tsvetkova et al. 2002)

Fig. 4

A sHSP primary sequence alignment by ClustalW algorithms using Jalview 2.11.2.5 software. Comparison of the alignments of 12 primary sHSP sequences described for their lipochaperone activity named “lipochaperone sHSP” with 38 primary sHSP sequences not described for this role named “Non lipochaperone sHSP.” Highly conserved (dark blue), conserved (blue), non-conserved (white), and unaligned (gray) residues are shown. Four domains, present on the β2 sheet (red arrow), before the β4 sheet (yellow arrow), β5 sheet (green arrow), and β7 sheet (blue arrow) respectively are more conserved on the lipochaperone sHSP. B Location of the four particularly conserved domains on a 3D predicted representation of an O. oeni sHSP Lo18 monomer

Fig. 5

Amino acid interaction distances in O. oeni sHSPf Lo18. A Interaction between the aromatic ring of tyrosine at position 107 (red) and its adjacent amino acids (blue) within an average radius of 3.6 Å or B interaction of the alanine at position 107 from the tyrosine mutation (red) with adjacent amino acids (blue) within an average radius of 5.925 Å. The loss of the aromatic ring alters the interaction distances with other amino acids