A Mechanism of Subunit Recruitment in Human Small Heat Shock Protein Oligomers

作者：Delbecq Scott P; Rosenbaum Joel C; Klevit Rachel E^*

来源：Biochemistry, 2015, 54(28): 4276-4284.

DOI：10.1021/acs.biochem.5b00490

Small beat shock proteins, (sHSPs) make up a class of molecular chaperones broadly observed,across organisms. Many sHSPs form large oligomers that undergo dynamic subunit,exchange that is thought tb play a role in chapetone function. Though remarkably heterogeneous, sHSP,oligomers share three tYpes of intermoletular interactions that involve all three defined tegions sHSP: the N-terminal region (NTR), the conserved alpha-crystallin domain (ACID), and a C-terminal region (CTR). Here we define the structural interactions involved in incorporation of a al:1)unit into a si-ISP oligomer. We demonstrate that a minimal ACD dimer of the human sHSP, HSPB5, interacts with an HSPB5 oligomer through two types of intetactions: (1) interactions with CTRs in the oligorner and (2) via exchange into and out of the diner interface composed of two ACDs. Unexpectedly, although dirners are thought to be the fundamental building block for sHSP' oligomers. Our results clearly indicate that subunit exchange into and out of oligorners occurs via monomers. Using structutebased mutants, we show that incorporation of a subunit into an oligorner is predicated on recruitment of the -subunit via its interaction with CTRs on an oligomer. Both the rate and extent of subunit incorporation depend on the accessibility-of CTRs within an HSPB5 oligomer. We Show that this mechanism also applies to formation of heterooligotheric sHSP Species composed of HSPB5 and HSPB6 and is likely general among sHSPs. Finally, our observations highlight the importance of NTRs in the thermodynamic stability of sEISP oligomers.

• 出版日期2015-7-21