Everything but the ACD, Functional Conservation of the Non-conserved Terminal Regions in sHSPs

Abstract

At the primary level small heat shock proteins are commonly described as a conserved α-crystallin domain fl anked by regions that have disparate sequence content. While this holds true when analysing simple pairwise alignments, it belittles the importance of these N-terminal and C-terminal extensions. Careful examination of their sequences, combined with an improved understanding of the structure and activity of these proteins, yields an alternative view where the N-and C-terminal arms play an important role in function. In this chapter we shall describe the current understanding of these two regions and highlight that they both demonstrate structural and functional properties that are highly conserved across all kingdoms of life.

The preferential heterodimerization of human small heat shock proteins HSPB1 and HSPB6 is dictated by the N-terminal domain

“…The various sHSP truncations ultimately point to the NTD, a region predicted to be unstructured [20,33], as being essential for driving the specific heterodimerization of HSPB1…”

“…The involvement of the NTD in defining the heterodimer interface, located at the ACD, is quite remarkable. Truncation or post-translational modification of this region often leads to smaller assemblies typically pointing to its recognized role in higher-order oligomerization rather than dimer formation [33]. It was reported that phosphorylation of the N-terminal serine residues of HSPB5 led to a loss of the dimeric substructure within the larger oligomer species, but this was hypothesized to be the result of a reduced interaction of individual subunits within the whole assembly [37].…”

“…The ACD has a -sandwich fold and is responsible for dimer formation, while the NTD and CTD are predicted to be disordered [20,33]. Limited proteolysis and X-ray crystallographic studies of vertebrate sHSPs, point to ACD as being the sole temporally stable structured region in these proteins [20,24,34].…”

“…This suggests the possibility of cross-talk between one or both of the NTDs and the heterodimer ACD, via a molecular mechanism that is absent in the homo-oligomeric species. Future experiments should attempt to discern the specific sequence epitopes that define this interaction, which appears non-trivial due to poor sequence conservation in the majority of the NTD [26,33]. [33].…”

“…Future experiments should attempt to discern the specific sequence epitopes that define this interaction, which appears non-trivial due to poor sequence conservation in the majority of the NTD [26,33]. [33]. The NTD and CTD for both constructs are shaded in gray.…”