The growing world of small heat shock proteins: from structure to functions

Abstract

Small heat shock proteins (sHSPs) are present in all kingdoms of life and play fundamental roles in cell biology. sHSPs are key components of the cellular protein quality control system, acting as the first line of defense against conditions that affect protein homeostasis and proteome stability, from bacteria to plants to humans. sHSPs have the ability to bind to a large subset of substrates and to maintain them in a state competent for refolding or clearance with the assistance of the HSP70 machinery. sHSPs participate in a number of biological processes, from the cell cycle, to cell differentiation, from adaptation to stressful conditions, to apoptosis, and, even, to the transformation of a cell into a malignant state. As a consequence, sHSP malfunction has been implicated in abnormal placental development and preterm deliveries, in the prognosis of several types of cancer, and in the development of neurological diseases. Moreover, mutations in the genes encoding several mammalian sHSPs result in neurological, muscular, or cardiac age-related diseases in humans. Loss of protein homeostasis due to protein aggregation is typical of many age-related neurodegenerative and neuromuscular diseases. In light of the role of sHSPs in the clearance of un/misfolded aggregation-prone substrates, pharmacological modulation of sHSP expression or function and rescue of defective sHSPs represent possible routes to alleviate or cure protein conformation diseases. Here, we report the latest news and views on sHSPs discussed by many of the world's experts in the sHSP field during a dedicated workshop organized in Italy (Bertinoro, CEUB, October 12-15, 2016).

FAIM opposes stress-induced loss of viability and blocks the formation of protein aggregates

“…Although there is no homology between FAIM and sHSPs, implying they have evolved independently, we found structural and biochemical similarities that suggest they contribute to some related common functions in cells. First, the predicted molecular weight of monomer FAIM ranges from 17-43 kDa throughout the evolution of holozoans while sHSPs have a similar monomeric molecular weight range of 15-40 kDa 34 . Second, three-dimensional protein analysis by NMR reveals that FAIM contains a rare compact non-interleaved seven stranded bsandwich structure with an anti-parallel b-sheet in the C-terminal region and a highly disordered N-terminal region, and experiences temperature-dependent conformational changes 15,35 .…”

Stress-Activated Chaperones: A First Line of Defense

“…One of these is the small heat shock proteins (sHsps), a diverse group of chaperones that play important roles in maintaining protein homeostasis in all kingdoms of life [75]. Stress-specific activation of their chaperone function has been observed for several members.…”

“…Once non-stress conditions have been restored, the client proteins can then be extracted and refolded by members of the Hsp70/Hsp104-system [27, 80]. Outstanding, very recent reviews are available that provide deeper mechanistic and regulatory insights into the chaperone function of sHsps [75, 81]…”

Hsp27 reduces glycation-induced toxicity and aggregation of α-synuclein

“…However, sHsps are not only involved in stress responses, but also in stress tolerance, cell death, differentiation, cell cycle, and signal transduction 29 . sHsps have also been reported to play a role in aging and protein aggregation disorders, such as neurodegenerative diseases like Alzheimer's disease and PD [30][31][32][33][34] .…”